owencqueen/cgbench_data huggingface dataset:
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS1 — Strong
Use with no specification.


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: PS2 — 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: PS2 — Strong
Use proposed SVI point recommendations.




Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant






Use only when proband has an additional pathogenic or likely pathogenic variant with the de novo variant. Additionally, the P/LP variant must have been classified as such by the Platelet VCEP.


Use ClinGen SVI’s proposed point recommendation table to determine the appropriate evidence code weight (see below). To be scored at the highest level with “Phenotype highly specific for gene” the proband must meet the PP4 criteria.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS2 — 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: PS3 — Strong
In a transgenic animal model, must demonstrate minimal to no function (flow cytometry JON/A, aggregation, or alternate assay analyzing integrin function) OR


In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced (>5% expression compared to WT), disruption of protein function must be demonstrated by significantly reduced binding to fibrinogen or ligand mimetic antibodies (e.g. PAC-1) OR (B) Absent surface protein expression (<5% expression compared to WT) shown by at least 1 of 2 of the following assays: flow cytometry or Western blotting.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PS3 — Moderate
In a model organism or heterologous cell line, significantly reduced surface protein expression (5-25% expression compared to WT) on at least 1 of 2 of the following assays: flow cytometry or Western blotting.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM2 — Supporting
Prevalence <1/10,000 (<0.0001) alleles in gnomAD.




This evidence code is available when a variant is present in fewer than 1 in 10,000 alleles in the ExAC or gnomAD population cohorts.


This cutoff was recommended based on work from Buitrago, et al showing that none of the established GT pathogenic variants were identified in ~32,000 alleles studies; suggesting that pathogenic variants have allele frequencies less than 0.01% in studied populations (PMID: 25827233)
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM4 — Moderate
This rule can be applied as originally intended by the ACMG/AMP guidelines.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM5 — Moderate
The strength of this rule may be adjusted based on the classification of the previously observed variant
Gene: ITGA2B (HGNC:6138)
Evidence Code: PM5 — Supporting
Use at adjusted strength. Novel missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.
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 — Moderate
Use proposed SVI point recommendations.




Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant




Use only when proband has a pathogenic or likely pathogenic variant in trans with the de novo variant.


Use ClinGen SVI’s proposed point recommendation table to determine the appropriate evidence code weight (see PS2). To be scored at the highest level with “Phenotype highly specific for gene” the patient must meet the PP4 criteria.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP3 — Supporting
REVEL score of > 0.7 OR >2 independent in silico missense predictors predict a damaging impact.


For missense variants:




REVEL score of > 0.7 is required for use of this rule code.
Buitrago et al. (PNAS 2015) reported that three commonly used computational algorithms (Polyphen, SIFT, and CADD) to predict Pathogenicity had a 69–98% sensitivity in detecting GT pathogenic variants. (PMID: 25827233).




For splicing variants:




>2 independent in silico missense predictors predict a damaging impact
We have used Human Splicing Finder and Maximum Entropy Scan with the following parameters: (1) the threshold for a position to be considered a splice site is >65 for HSF and >3 for MaxEntScan, (2) a broken splice site is defined as a position that has shifted below the threshold with a difference in score of <-10% for HSF or <-30% for MaxEntScan, and (3) a new splice site is defined as a position that has shifted above the threshold where the difference in score is >10% for HSF or >30% for MaxEntScan.
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. Full sequencing of both genes is required at this strength.
Gene: ITGA2B (HGNC:6138)
Evidence Code: PP4 — Supporting
Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities.
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).




Use a minor allele frequency cutoff of >0.00158 but <0.0024 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.


To set the strong MAF cutoff, we use the rationale discussed above and accounted for the two known genes associated with GT; whereas the above calculation assumed only one causative gene.
Gene: ITGA2B (HGNC:6138)
Evidence Code: BS2 — Strong
>1 homozygote who is unaffected proven with at least aggregometry.




This evidence code is available when the variant is identified in >1 homozygotes who are unaffected (proven with at least aggregometry).


It is important to note that in order to use this rule one must have phenotypic information about an individual who is homozygous for a particular variant. This means one could not use population data (i.e. gnomAD or ExAC) as evidence. This code would more likely be used in the setting of gene panel testing, where an individual with a different phenotype was found to be homozygous for a variant in one of those two genes.
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: BP3 — Supporting
This rule can be applied as originally intended by the ACMG/AMP guidelines in the ITG3B gene, which has three repetitive microsatellite regions. There are no known repetitive regions in the ITGA2B gene.
Gene: ITGA2B (HGNC:6138)
Evidence Code: BP4 — Supporting
REVEL score of < 0.25.


Use this code for missense variants with a REVEL score of < 0.25.
● This recommendation was based on evaluating the REVEL scores of variants assessed as benign by this VCEP using our rule specifications with the exception of this rule code. All benign and likely benign variants fell under this threshold.
● We are not recommending the use of other missense in silico model predictors at this time due to a previous concern about their validity for these genes as demonstrated by Buitrago et al. (PNAS 2015). They found that the three computational algorithms they used were less reliable predicting non-pathogenicity of previously known benign variants. (PMID: 25827233)
Gene: ITGA2B (HGNC:6138)
Evidence Code: BP7 — Supporting
Use with no specification. This rule can be applied as originally intended by the ACMG/AMP guidelines.