{"interpretationByValue":{},"identifier":"acgs-clingen","name":"ACGS 2020 + ClinGen Recommendations","description":"Combination of ACGS Recommendations and more recent ClinGen publications.","version":"2023","interpretations":[{"name":"Pathogenic","value":5,"description":"Variant is definitively causative for disease"},{"name":"Likely Pathogenic","value":4,"description":"Variant is very likely causative for disease"},{"name":"Uncertain Significance","value":3,"description":"Not enough information available"},{"name":"Likely Benign","value":2,"description":"Variant is likely benign"},{"name":"Benign","value":1,"description":"Variant is benign"}],"criteria":[{"allCategories":[],"name":"PVS1_VS","description":"Undergoes NMD (based on any mechanism) in biologically relevant transcript or full gene deletion.","categories":["PVS1"],"value":8},{"allCategories":[],"name":"PVS1_S","description":"Non-NMD: Altered region critical to protein function. Or LoF variants infrequent in general population and Variant removes >10% of protein.","categories":["PVS1"],"value":4},{"allCategories":[],"name":"PVS1_M","description":"Non-NMD: LoF variants infrequent in population and change removes <10% of protein.","categories":["PVS1"],"value":2},{"allCategories":[],"name":"PS1_S","description":"Same AA change with different nucleotide change - do not confuse with PM5","categories":["PS1"],"value":4},{"allCategories":[],"name":"PS1_M","description":"For start codon variants","categories":["PS1"],"value":2},{"allCategories":[],"name":"PS1_P","description":"different intronic change with same or more severe splicing effect","categories":["PS1"],"value":1},{"allCategories":[],"name":"PS2_VS","description":">=4 Points - based on:\n2 (phenotype highly specific for gene)\n1 (phenotype consistent)\n0.5 (high genetic heterogeneity)\nhalve for assumed de-novo; score summed for each proband","categories":["PS2"],"value":8},{"allCategories":[],"name":"PS2_S","description":">=2 Points - based on:\n2 (phenotype highly specific for gene)\n1 (phenotype consistent)\n0.5 (high genetic heterogeneity)\nhalve for assumed de-novo; score summed for each proband","categories":["PS2"],"value":4},{"allCategories":[],"name":"PS2_M","description":">=1 Points - based on:\n2 (phenotype highly specific for gene)\n1 (phenotype consistent)\n0.5 (high genetic heterogeneity)\nhalve for assumed de-novo; score summed for each proband","categories":["PS2"],"value":2},{"allCategories":[],"name":"PS2_P","description":">=0.5 Points - based on:\n2 (phenotype highly specific for gene)\n1 (phenotype consistent)\n0.5 (high genetic heterogeneity)\nhalve for assumed de-novo; score summed for each proband","categories":["PS2"],"value":1},{"allCategories":[],"name":"PS3_S","description":"depending on strength of evidence, use at lower eg if only one reference is available","categories":["PS3"],"value":4},{"allCategories":[],"name":"PS3_M","description":"depending on strength of evidence, use at lower eg if only one reference is available","categories":["PS3"],"value":2},{"allCategories":[],"name":"PS3_P","description":"depending on strength of evidence, use at lower eg if only one reference is available","categories":["PS3"],"value":1},{"allCategories":[],"name":"PS4_S","description":"Relative risk or OR from case-control studies is >5.0 and confidence interval does not include 1.0.","categories":["PS4"],"value":4},{"allCategories":[],"name":"PS4_M","description":"Variant previously identified in >=2 unrelated affected individuals and not in gnomAD (or extremely low frequency if AR)","categories":["PS4"],"value":2},{"allCategories":[],"name":"PS4_P","description":"Variant previously identified in 1 unrelated affected individuals and not in gnomAD (or extremely low frequency if AR)\nVariant previously identified in >=2 unrelated affected individuals, but is not absent in controls","categories":["PS4"],"value":1},{"allCategories":[],"name":"PM1_S","description":"Very specific residues that are critical for protein structure or function.","categories":["PM1"],"value":4},{"allCategories":[],"name":"PM1_M","description":"Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation","categories":["PM1"],"value":2},{"allCategories":[],"name":"PM1_P","description":"Some benign missense variation present or supporting evidence in silico protein modelling results","categories":["PM1"],"value":1},{"allCategories":[],"name":"PM2_P","description":"Absent for dominant disease, for recessive should be below the expected carrier frequency. Variant in gnomAD needs to be covered by sufficient read depth/quality.","categories":["PM2"],"value":1},{"allCategories":[],"name":"PM3_S","description":"Multiple observations of the variant in trans with (likely) pathongenic variants.","categories":["PM3"],"value":4},{"allCategories":[],"name":"PM3_M","description":"Requires confirmation of phase by testing of parents.","categories":["PM3"],"value":2},{"allCategories":[],"name":"PM3_P","description":"Can also be used for homozygous variants, but always downgrade by one level.","categories":["PM3"],"value":1},{"allCategories":[],"name":"PM4_M","description":"Multiple AA in-frame deletion/insertion.","categories":["PM4"],"value":2},{"allCategories":[],"name":"PM4_P","description":"Single AA in-frame deletion/insertion.","categories":["PM4"],"value":1},{"allCategories":[],"name":"PM5_S","description":"multiple observations of different pathogenic variants at the same residue","categories":["PM5"],"value":4},{"allCategories":[],"name":"PM5_M","description":"different missense change determined to be pathogenic","categories":["PM5"],"value":2},{"allCategories":[],"name":"PM5_P","description":"single case with likely pathonic classification described.","categories":["PM5"],"value":1},{"allCategories":[],"name":"PM6_VS","description":">=4 Points - based on:\n2 (phenotype highly specific for gene)\n1 (phenotype consistent)\n0.5 (high genetic heterogeneity)\nhalve for assumed de-novo; score summed for each proband","categories":["PM6"],"value":8},{"allCategories":[],"name":"PM6_S","description":">=2 Points - based on:\n2 (phenotype highly specific for gene)\n1 (phenotype consistent)\n0.5 (high genetic heterogeneity)\nhalve for assumed de-novo; score summed for each proband","categories":["PM6"],"value":4},{"allCategories":[],"name":"PM6_M","description":">=1 Points - based on:\n2 (phenotype highly specific for gene)\n1 (phenotype consistent)\n0.5 (high genetic heterogeneity)\nhalve for assumed de-novo; score summed for each proband","categories":["PM6"],"value":2},{"allCategories":[],"name":"PM6_P","description":">=0.5 Points - based on:\n2 (phenotype highly specific for gene)\n1 (phenotype consistent)\n0.5 (high genetic heterogeneity)\nhalve for assumed de-novo; score summed for each proband","categories":["PM6"],"value":1},{"allCategories":[],"name":"PP1_S","description":"N <= 1/32 or N <= 1/16 if more than 1 family","categories":["PP1"],"value":4},{"allCategories":[],"name":"PP1_M","description":"N <= 1/16 or N <= 1/8 if more than 1 family","categories":["PP1"],"value":2},{"allCategories":[],"name":"PP1_P","description":"N <= 1/8 or N <= 1/4 if more than 1 family","categories":["PP1"],"value":1},{"allCategories":[],"name":"PP2_P","description":"Z-Score >= 3.09 or Regional Missense Constraint < 0.6 (Samocha 2017)","categories":["PP2"],"value":1},{"allCategories":[],"name":"PP3_S","description":"REVEL >= 0.932\nBayesDel >= 0.5","categories":["PP3"],"value":4},{"allCategories":[],"name":"PP3_M","description":"REVEL >= 0.773\nBayesDel >= 0.27\nCADD >= 28.1","categories":["PP3"],"value":2},{"allCategories":[],"name":"PP3_P","description":"REVEL >= 0.644\nBayesDel >= 0.13\nCADD >= 25.3","categories":["PP3"],"value":1},{"allCategories":[],"name":"PP4_S","description":"e.g. IDS for MPS II or CAPN3 for Calpainopathy","categories":["PP4"],"value":4},{"allCategories":[],"name":"PP4_M","description":"e.g. NIPBL in CdL or Sotos and Gorlin with typical gestalt and gene","categories":["PP4"],"value":2},{"allCategories":[],"name":"PP4_P","description":"e.g. typical gene but less distinct phenotype","categories":["PP4"],"value":1},{"allCategories":[],"name":"PP5_P","description":"ClinGen SVI recommends that PP5 should not be used.","categories":["PP5"],"value":1},{"allCategories":[],"name":"BA1_SA","description":"","categories":["BA1"],"value":-8},{"allCategories":[],"name":"BS1_SA","description":"For AD disorder with high penetrance","categories":["BS1"],"value":-8},{"allCategories":[],"name":"BS1_S","description":"Frequency above disease incidence","categories":["BS1"],"value":-4},{"allCategories":[],"name":"BS2_S","description":"gnomAD only doesn't contain severe pediatric disease, so not truly reliable here","categories":["BS2"],"value":-4},{"allCategories":[],"name":"BS3_S","description":"in vitro assays or mRNA analysis","categories":["BS3"],"value":-4},{"allCategories":[],"name":"BS4_S","description":"","categories":["BS4"],"value":-4},{"allCategories":[],"name":"BP1_P","description":"can also be used in reverse for LoF in mostly gain-of-function disease","categories":["BP1"],"value":-1},{"allCategories":[],"name":"BP2_SA","description":"can be used for well-established AD disease models, such as CFTR variants","categories":["BP2"],"value":-8},{"allCategories":[],"name":"BP2_P","description":"","categories":["BP2"],"value":-1},{"allCategories":[],"name":"BP3_P","description":"","categories":["BP3"],"value":-1},{"allCategories":[],"name":"BP4_P","description":"","categories":["BP4"],"value":-1},{"allCategories":[],"name":"BP5_P","description":"","categories":["BP5"],"value":-1},{"allCategories":[],"name":"BP6_P","description":"The ClinGen SVI group recommends that PP5 and BP6 criterion should not be used","categories":["BP6"],"value":-1},{"allCategories":[],"name":"BP7_P","description":"","categories":["BP7"],"value":-1}],"categories":[{"name":"pathogenic","description":"Pathogenic criteria","longDescription":"","type":"Direction","order":0,"categories":[]},{"name":"benign","description":"Benign criteria","longDescription":"","type":"Direction","order":1,"categories":[]},{"name":"SA","description":"Standalone","longDescription":"","type":"Strength","order":-1,"categories":[]},{"name":"VS","description":"very strong","longDescription":"","type":"Strength","order":0,"categories":[]},{"name":"S","description":"strong","longDescription":"","type":"Strength","order":1,"categories":[]},{"name":"M","description":"moderate","longDescription":"","type":"Strength","order":2,"categories":[]},{"name":"P","description":"supporting","longDescription":"","type":"Strength","order":3,"categories":[]},{"name":"functional","description":"Functional criteria","longDescription":"","type":"Mechanism","order":0,"categories":[]},{"name":"frequency","description":"Functional criteria","longDescription":"","type":"Mechanism","order":1,"categories":[]},{"name":"literature","description":"Functional criteria","longDescription":"","type":"Mechanism","order":2,"categories":[]},{"name":"inheritance","description":"Functional criteria","longDescription":"","type":"Mechanism","order":3,"categories":[]},{"name":"combination","description":"Functional criteria","longDescription":"","type":"Mechanism","order":4,"categories":[]},{"name":"PVS1","description":"Null variant","longDescription":"Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease. (see Tayoun 2018)","type":"Criteria","order":0,"categories":["pathogenic","functional","VS"]},{"name":"PS1","description":"literature: this AA exchange","longDescription":"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. For same base change use PS4 criteria instead.","type":"Criteria","order":0,"categories":["pathogenic","literature","S"]},{"name":"PS2","description":"<u>confirmed</u> de novo","longDescription":"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. (see ACGS Clingen 2019)","type":"Criteria","order":0,"categories":["pathogenic","inheritance","S"]},{"name":"PS3","description":"supported by functional studies","longDescription":"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product","type":"Criteria","order":0,"categories":["pathogenic","functional","S"]},{"name":"PS4","description":"prevalence in disease &gt; controls","longDescription":"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls","type":"Criteria","order":0,"categories":["pathogenic","frequency","S"]},{"name":"PM1","description":"variant in hotspot (missense)","longDescription":"Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation","type":"Criteria","order":0,"categories":["pathogenic","functional","M"]},{"name":"PM2","description":"rare; &lt; 1:20.000 in ExAC","longDescription":"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium","type":"Criteria","order":0,"categories":["pathogenic","frequency","M"]},{"name":"PM3","description":"AR: <i>trans</i> with known pathogenic","longDescription":"For recessive disorders, detected in trans with a pathogenic variant. Use BP2 if in-cis with pathogenic variant and also for variants in-trans for dominant disease.","type":"Criteria","order":0,"categories":["pathogenic","combination","M"]},{"name":"PM4","description":"protein length change","longDescription":"Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants. Do not combine with PVS1 or PP3.","type":"Criteria","order":0,"categories":["pathogenic","functional","M"]},{"name":"PM5","description":"literature: AA exchange same pos","longDescription":"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before","type":"Criteria","order":0,"categories":["pathogenic","literature","M"]},{"name":"PM6","description":"<u>assumed</u> de novo","longDescription":"Assumed de novo, but without confirmation of paternity and maternity. Do not use in combination with PS2, use either.","type":"Criteria","order":0,"categories":["pathogenic","inheritance","M"]},{"name":"PP1","description":"cosegregates in family","longDescription":"Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease, computed by number of informative meioses (see Jarvik 2016)","type":"Criteria","order":0,"categories":["pathogenic","inheritance","P"]},{"name":"PP2","description":"few missense in gene","longDescription":"Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease","type":"Criteria","order":0,"categories":["pathogenic","frequency","P"]},{"name":"PP3","description":"predicted pathogenic &geq; 2","longDescription":"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)","type":"Criteria","order":0,"categories":["pathogenic","functional","P"]},{"name":"PP4","description":"phenotype/pedigree match gene","longDescription":"Patient's phenotype or family history is highly specific for a disease with a single genetic etiology (Pejaver 2022)","type":"Criteria","order":0,"categories":["pathogenic","inheritance","P"]},{"name":"PP5","description":"reliable source: pathogenic","longDescription":"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation","type":"Criteria","order":0,"categories":["pathogenic","literature","P"]},{"name":"BA1","description":"allele frequency &gt; 5%","longDescription":"Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium","type":"Criteria","order":0,"categories":["benign","frequency","VS"]},{"name":"BS1","description":"disease: allele freq. too high","longDescription":"Allele frequency is greater than expected for disorder","type":"Criteria","order":0,"categories":["benign","frequency","S"]},{"name":"BS2","description":"observed in healthy individual","longDescription":"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age","type":"Criteria","order":0,"categories":["benign","inheritance","S"]},{"name":"BS3","description":"functional studies: benign","longDescription":"Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing","type":"Criteria","order":0,"categories":["benign","functional","S"]},{"name":"BS4","description":"lack of segregation","longDescription":"Lack of segregation in affected members of a family","type":"Criteria","order":0,"categories":["benign","inheritance","S"]},{"name":"BP1","description":"missense in truncation gene","longDescription":"Missense variant in a gene for which primarily truncating variants are known to cause disease","type":"Criteria","order":0,"categories":["benign","functional","P"]},{"name":"BP2","description":"other variant is causative","longDescription":"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern","type":"Criteria","order":0,"categories":["benign","combination","P"]},{"name":"BP3","description":"in-frame indel in repeat","longDescription":"In-frame deletions/insertions in a repetitive region without a known function. Do not combine with BP4.","type":"Criteria","order":0,"categories":["benign","functional","P"]},{"name":"BP4","description":"prediction: benign","longDescription":"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). Can be used with BP7 for weakly conserved nucleotides without splicing impact.","type":"Criteria","order":0,"categories":["benign","functional","P"]},{"name":"BP5","description":"different gene in other case","longDescription":"Variant found in a case with an alternate molecular basis for disease","type":"Criteria","order":0,"categories":["benign","combination","P"]},{"name":"BP6","description":"reputable source: benign","longDescription":"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation","type":"Criteria","order":0,"categories":["benign","literature","P"]},{"name":"BP7","description":"silent, no splicing/conservation","longDescription":"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Can be used in combination with BP4.","type":"Criteria","order":0,"categories":["benign","functional","P"]}],"rules":[{"value":5,"combinationOccurences":{},"combination":[8,4]},{"value":5,"combinationOccurences":{},"combination":[8,2]},{"value":5,"combinationOccurences":{},"combination":[8,1,1]},{"value":5,"combinationOccurences":{},"combination":[4,4,4]},{"value":5,"combinationOccurences":{},"combination":[4,4,2]},{"value":5,"combinationOccurences":{},"combination":[4,4,1,1]},{"value":5,"combinationOccurences":{},"combination":[4,2,2,2]},{"value":5,"combinationOccurences":{},"combination":[4,2,2,1,1]},{"value":5,"combinationOccurences":{},"combination":[4,2,1,1,1,1]},{"value":4,"combinationOccurences":{},"combination":[8,1]},{"value":4,"combinationOccurences":{},"combination":[4,4]},{"value":4,"combinationOccurences":{},"combination":[4,2]},{"value":4,"combinationOccurences":{},"combination":[4,1,1]},{"value":4,"combinationOccurences":{},"combination":[2,2,2]},{"value":4,"combinationOccurences":{},"combination":[2,2,1,1]},{"value":4,"combinationOccurences":{},"combination":[2,1,1,1,1]},{"value":1,"combinationOccurences":{},"combination":[-8]},{"value":1,"combinationOccurences":{},"combination":[-4,-4]},{"value":2,"combinationOccurences":{},"combination":[-4,-1]},{"value":2,"combinationOccurences":{},"combination":[-1,-1]},{"value":3,"combinationOccurences":{},"combination":[]}],"lints":[{"value":2,"description":"PS2 and PM6 cannot be used simultaneously.","categoryConditions":["PS2","PM6"]},{"value":2,"description":"BP4 and BP3 cannot be used simultaneously.","categoryConditions":["BP4","BP3"]},{"value":2,"description":"PVS1 and PM4 cannot be used simultaneously.","categoryConditions":["PVS1","PM4"]},{"value":2,"description":"PVS1 and PP3 cannot be used simultaneously.","categoryConditions":["PVS1","PP3"]},{"value":2,"description":"PM4 and PP3 cannot be used simultaneously.","categoryConditions":["PM4","PP3"]},{"value":2,"description":"PM1 and PP3 sum of evidence should not exceed strong.","callbackConditions":[null]},{"value":1,"description":"Using PP5 is highly discouraged by ACGS ClinGen.","categoryConditions":["PP5"]},{"value":1,"description":"Using BP6 is highly discouraged by ACGS ClinGen.","categoryConditions":["BP6"]}]}