chr17-44372390-C-CCA

Position:

• chr17-44372390-C-CCA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM4 PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.5(ITGA2B):c.3092_3093dup variant results in a frameshift, p.Glu1032TrpfsTer98, and introduction of a stop codon further than the original. This adds 90 amino acids to the ITGA2B protein. The variant is absent from population databases, including gnomADv2.1.1 (PM2_supporting). It is reported in a compound heterozygous individual with the c.3060+2T>C variant (classified Pathogenic by the PD VCEP; PM3_supporting); however, the individual does not meet criteria for PP4 (PMID:9215749). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, BP4 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA500260678/MONDO:0010119/011

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: ITGA2B NM_000419.5 frameshift
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: -0.405

Genes affected

ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.3093_3094insTG	p.Glu1032TrpfsTer?	frameshift_variant	30/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.3144_3145insTG	p.Glu1049TrpfsTer?	frameshift_variant	29/29
ITGA2B	XM_011524750.2	c.3129_3130insTG	p.Glu1044TrpfsTer?	frameshift_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3093_3094insTG	p.Glu1032TrpfsTer?	frameshift_variant	30/30	1	NM_000419.5	P1
ITGA2B	ENST00000587295.5	c.286_287insTG	p.Glu97TrpfsTer?	frameshift_variant	3/3	3
ITGA2B	ENST00000648408.1	c.2407_2408insTG	p.Glu804TrpfsTer?	frameshift_variant	25/25

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Jun 01, 2023	The NM_000419.5(ITGA2B):c.3092_3093dup variant results in a frameshift, p.Glu1032TrpfsTer98, and introduction of a stop codon further than the original. This adds 90 amino acids to the ITGA2B protein. The variant is absent from population databases, including gnomADv2.1.1 (PM2_supporting). It is reported in a compound heterozygous individual with the c.3060+2T>C variant (classified Pathogenic by the PD VCEP; PM3_supporting); however, the individual does not meet criteria for PP4 (PMID: 9215749). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, BP4 (PD VCEP specifications version 2.1). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the C-terminus of the ITGA2B protein. Other variant(s) that disrupt this region (p.*1040Trpext*) have been observed in individuals with ITGA2B-related conditions (PMID: 19691478). This suggests that this may be a clinically significant region of the protein. ClinVar contains an entry for this variant (Variation ID: 953020). This variant is also known as 3094insTG. This frameshift has been observed in individual(s) with Glanzmann Thrombasthenia (PMID: 9215749). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the ITGA2B gene (p.Glu1032Trpfs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acids of the ITGA2B protein and extend the protein. -

Platelet-type bleeding disorder 16 Pathogenic:1

Pathogenic, no assertion criteria provided

research

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2048504826; hg19: chr17-42449758;