chr17-44372390-C-CCA

Variant names:

• chr17-44372390-C-CCA
• rs2048504826
• NM_000419.5:c.3092_3093dupTG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2_Supporting PM4 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:2 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.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2B	NM_000419.5	c.3092_3093dupTG	p.Glu1032TrpfsTer70	frameshift_variant	Exon 30 of 30	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2	c.3143_3144dupTG	p.Glu1049TrpfsTer70	frameshift_variant	Exon 29 of 29		XP_011523051.2
ITGA2B	XM_011524750.2	c.3128_3129dupTG	p.Glu1044TrpfsTer70	frameshift_variant	Exon 29 of 29		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6	c.3092_3093dupTG	p.Glu1032TrpfsTer70	frameshift_variant	Exon 30 of 30	1	NM_000419.5	ENSP00000262407.5
ITGA2B	ENST00000648408.1	c.2405_2406dupTG	p.Glu803fs	frameshift_variant	Exon 25 of 25			ENSP00000498119.1
ITGA2B	ENST00000587295.5	c.284_285dupTG	p.Glu96fs	frameshift_variant	Exon 3 of 3	3		ENSP00000467269.1

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:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:2

Jan 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 01, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Platelet-type bleeding disorder 16 Pathogenic:1

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Platelet-type bleeding disorder 16;CN300358:Glanzmann thrombasthenia 1 Pathogenic:1

Mar 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;