chr17-44378360-A-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2_SupportingPM3_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.2094+2T>C splice variant is predicted to cause skipping of exon 20, introducing a premature termination codon, and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual reported to have Glanzmann's thrombasthenia (GT), however sufficient phenotype information was not provided to determine if the individual's phenotype is specific for GT. This variant is absent from population databases, including gnomAD. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, and PM3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA399799489/MONDO:0010119/011
Frequency
Consequence
NM_000419.5 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGA2B | NM_000419.5 | c.2094+2T>C | splice_donor_variant | ENST00000262407.6 | |||
ITGA2B | XM_011524749.2 | c.2247+2T>C | splice_donor_variant | ||||
ITGA2B | XM_011524750.2 | c.2247+2T>C | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGA2B | ENST00000262407.6 | c.2094+2T>C | splice_donor_variant | 1 | NM_000419.5 | P1 | |||
ITGA2B | ENST00000648408.1 | c.1525+2T>C | splice_donor_variant | ||||||
ITGA2B | ENST00000592462.5 | n.889+2T>C | splice_donor_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glanzmann thrombasthenia Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | May 07, 2021 | The NM_000419.5(ITGA2B):c.2094+2T>C splice variant is predicted to cause skipping of exon 20, introducing a premature termination codon, and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in one individual reported to have Glanzmann's thrombasthenia (GT), however sufficient phenotype information was not provided to determine if the individual's phenotype is specific for GT. This variant is absent from population databases, including gnomAD. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, and PM3_supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 12, 2021 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with Glanzmann thrombasthenia (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 458368). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 20 of the ITGA2B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ITGA2B are known to be pathogenic (PMID: 21917754). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at