owencqueen/cgbench_data huggingface dataset:
Gene: ITGA2B (HGNC:6138)
Evidence Code: PVS1 — Original ACMG Summary
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Caveats:
 • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7)
 • Use caution interpreting LOF variants at the extreme 3’ end of a gene
 • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact
 • Use caution in the presence of multiple transcripts
Gene: ITGA2B (HGNC:6138)
Evidence Code: PVS1 — Very Strong
Use decision tree as per SVI WG with specified “regions critical to protein function”.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS1 — Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS1 — Strong
Use with no specification.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS2 — Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS2 — Strong
Use proposed SVI point recommendations.




Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS2 — Moderate
Use proposed SVI point recommendations.




Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS3 — Strong
In a transgenic animal model, must demonstrate minimal to no function.
OR


In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced, disruption of protein function must be demonstrated OR (B) Absent surface protein expression (<5%).
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS3 — Moderate
In a model organism or heterologous cell line, significantly reduced surface protein expression (5-25%).
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS4 — Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS4 — Strong
Rule does not apply due to rarity of disorder and lack of appropriate studies.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM1 — Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM1 — Moderate
Rule does not apply due to genes being highly polymorphic.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM2 — Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium
Caveat: Population data for indels may be poorly called by next generation sequencing
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM2 — Moderate
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM2 — Supporting
Prevalence <1/10,000 (<0.0001) alleles in gnomAD.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM3 — Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM3 — Very Strong
Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM3 — Strong
Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM3 — Moderate
Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM3 — Supporting
Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM4 — Moderate
Use with no specification.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM5 — Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Example: Arg156His is pathogenic; now you observe Arg156Cys
Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM5 — Moderate
Use with no specification.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM5 — Supporting
Use at adjusted strength.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM6 — Very Strong
Use proposed SVI point recommendations.




Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM6 — Strong
Use proposed SVI point recommendations.




Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM6 — Moderate
Use proposed SVI point recommendations.




Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM6 — Supporting
Use proposed SVI point recommendations.




Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP1 — Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
Note: May be used as stronger evidence with increasing segregation data
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP1 — Strong
Segregations in proband plus >2 affected relatives.




Affected relatives must have both variants identified in proband.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP1 — Moderate
Segregation in proband plus 2 affected relatives.




Affected relatives must have both variants identified in proband.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP1 — Supporting
Segregation in proband plus 1 affected relative.




Affected relatives must have both variants identified in proband.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP2 — Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP3 — Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the 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 should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP3 — Supporting
REVEL score of ≥ 0.7 OR >2 independent in silico missense predictors predict a damaging impact.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP4 — Strong
Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP4 — Moderate
Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP4 — Supporting
Patients phenotype or family history is highly specific for a disease with a single genetic etiology
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP5 — Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Gene: ITGA2B (HGNC:6138)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium
Gene: ITGA2B (HGNC:6138)
Evidence Code: BA1 — Stand Alone
Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles).
Gene: ITGA2B (HGNC:6138)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: ITGA2B (HGNC:6138)
Evidence Code: BS1 — Strong
Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles)
Gene: ITGA2B (HGNC:6138)
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: ITGA2B (HGNC:6138)
Evidence Code: BS2 — Strong
1 homozygote who is unaffected proven with at least aggregometry.
Gene: ITGA2B (HGNC:6138)
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: ITGA2B (HGNC:6138)
Evidence Code: BS3 — Strong
Must demonstrate normal aggregometry in a transgenic mouse model.
 OR


In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function
Gene: ITGA2B (HGNC:6138)
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: ITGA2B (HGNC:6138)
Evidence Code: BS4 — Strong
Variant not detected in an affected family member.
Gene: ITGA2B (HGNC:6138)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease
Gene: ITGA2B (HGNC:6138)
Evidence Code: BP1 — Supporting
Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.
Gene: ITGA2B (HGNC:6138)
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: ITGA2B (HGNC:6138)
Evidence Code: BP2 — Supporting
Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant)
Gene: ITGA2B (HGNC:6138)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: ITGA2B (HGNC:6138)
Evidence Code: BP3 — Supporting
Use with no specification
Gene: ITGA2B (HGNC:6138)
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: ITGA2B (HGNC:6138)
Evidence Code: BP4 — Supporting
REVEL score of < 0.25
Gene: ITGA2B (HGNC:6138)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: ITGA2B (HGNC:6138)
Evidence Code: BP5 — Supporting
Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.
Gene: ITGA2B (HGNC:6138)
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: ITGA2B (HGNC:6138)
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: ITGA2B (HGNC:6138)
Evidence Code: BP7 — Supporting
Use with no specification.