17-44372407-CG-GC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000419.5(ITGA2B):c.3076_3077delinsGC(p.Arg1026Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1026Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 4.08

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Integrin alpha-IIb light chain, form 1 (size 148) in uniprot entity ITA2B_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_000419.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44372408-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 50233.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=7, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2B	NM_000419.5	c.3076_3077delinsGC	p.Arg1026Ala	missense_variant	30/30	ENST00000262407.6
ITGA2B	XM_011524749.2	c.3127_3128delinsGC	p.Arg1043Ala	missense_variant	29/29
ITGA2B	XM_011524750.2	c.3112_3113delinsGC	p.Arg1038Ala	missense_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3076_3077delinsGC	p.Arg1026Ala	missense_variant	30/30	1	NM_000419.5	P1
ITGA2B	ENST00000587295.5	c.269_270delinsGC	p.Arg91Ala	missense_variant	3/3	3
ITGA2B	ENST00000648408.1	c.2390_2391delinsGC	p.Arg798Ala	missense_variant	25/25

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Nov 02, 2023

The NM_000419.5:c.3076_3077delinsGC results in a missense change, Arg1026Ala. The variant is absent gnomAD v2.1.1 and v3. PMID: 12575292 reports on the variant, but the evidence does not meet GT criteria for phenotype or functional studies. In summary, there is insufficient evidence at this time to classify this variant. GT-specific criteria met: PM2_Supporting. -

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: rs2048505090; hg19: chr17-42449775;