owencqueen/cgbench_data huggingface dataset:
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Allele frequency is 
≥0.001
 based on the 
filtering allele frequency (FAF)
 in 
gnomAD
 in the subpopulation with the highest frequency (popmax).


The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).


The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 


gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
CardioDB website
.




Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  


Set confidence to 0.95 (95%).


If the FAF is ≥0.001, this rule can be applied.




The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.


Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific,Gene-specific
Allele frequency is 
≥0.0002 for
 
MYBPC3
 based on the 
filtering allele frequency (FAF)
 in 
gnomAD
 in the subpopulation with the highest frequency (popmax).


Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
et al.
 2018
18
; Tavtigian 
et al.
 2020
19
). 


See BA1 for additional specifications that also apply to BS1.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS2 — Original ACMG Summary
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.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific
See PS3 specifications.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS3 — Moderate
Modification Type: Disease-specific
See PS3 specifications.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific
See PS3 specifications.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS4 — Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BS4 — Strong
Modification Type: Disease-specific
Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 




The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 


Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.




Because of these possibilities, 
multiple (≥2) non-segregations
 that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
are required to apply this rule
.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).


Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP2 — Original ACMG Summary
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.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
Other variants must be pathogenic as defined by these specifications.


Testing of parents or other informative relatives is often required to determine 
cis
/
trans
 status.


If a variant is seen in 
trans
 (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).




<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
et al.
 2015
20
).




This rule cannot be applied when the variant has only been observed in 
cis
 with a pathogenic variant as its significance in isolation is unknown in this scenario. 


Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP4 — Original ACMG Summary
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
As many 
in silico
 algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.


Use of REVEL (Ioannidis 
et al.
 2016
17
) is recommended at thresholds of 
≤0.40 for BP4
.


Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.


Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.


SpliceAI
2
 is recommended for evaluation of predicted splice impacts.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP6 — Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP7 — Original ACMG Summary
A synonymous 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.
Gene: MYBPC3 (HGNC:7551)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
Also applicable to 
intronic variants outside the splice consensus sequence (-4 and +7 outward)
 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.


Rule can be combined with BP4 to make a variant likely benign per Richards 
et al.
 2015
6
.