chr17-44375719-G-C

Position:

chr17-44375719-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM3PM4PP4_StrongPM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000419.4:c.2602-3C>G variant is a splice region variant that is predicted to result in abnormal splicing and is shown to skip exon 26 in RNA studies from a patient (PMID:1317725), resulting in an in-frame deletion of Val868 to Val909 (3.9% of the protein; PM4). It occurs at a low frequency in gnomADv2.1.1 with a MAF of 0.00006523 in the East Asian population (PM2_supporting). At least 3 compound heterozygous probands are reported in the literature, with the other variants being Leu973AlafsTer63, Leu214Pro, and Ala777Asp (PMID:15748238, PMID:27696190, PMID:29675921; PM3). In summary, based on the available evidence at this time, the c.2602-3C>G variant is classified as likely pathogenic. GT-specific criteria applied: PM2_supporting, PM3, PM4, PP4_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10575472/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

ITGA2B
ENST00000262407.6 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9972

Clinical Significance

Likely pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 0.978

Variant links:

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]

ITGA2B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
ITGA2B	NM_000419.5 linkuse as main transcript	c.2602-3C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000262407.6	NP_000410.2
ITGA2B	XM_011524749.2 linkuse as main transcript	c.2755-3C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		XP_011523051.2
ITGA2B	XM_011524750.2 linkuse as main transcript	c.2755-3C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		XP_011523052.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
ITGA2B	ENST00000262407.6 linkuse as main transcript	c.2602-3C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_000419.5	ENSP00000262407	P1	P08514-1
ITGA2B	ENST00000587295.5 linkuse as main transcript	c.253+114C>G	intron_variant	3		ENSP00000467269
ITGA2B	ENST00000648408.1 linkuse as main transcript	c.2033-3C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			ENSP00000498119
ITGA2B	ENST00000592462.5 linkuse as main transcript	n.1397-3C>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000551

AC:

AN:

181340

Hom.:

AF XY:

0.0000103

AC XY:

AN XY:

97246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000726

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000563

AC:

AN:

1420694

Hom.:

Cov.:

AF XY:

0.00000569

AC XY:

AN XY:

703150

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000158

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.17e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 26, 2022	Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 26, but is expected to preserve the integrity of the reading-frame (PMID: 1317725). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2893). This variant has been observed in individual(s) with Glanzmann thrombasthenia (PMID: 1317725, 29675921). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change falls in intron 25 of the ITGA2B gene. It does not directly change the encoded amino acid sequence of the ITGA2B protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Sep 07, 2023	The NM_000419.4:c.2602-3C>G variant is a splice region variant that is predicted to result in abnormal splicing and is shown to skip exon 26 in RNA studies from a patient (PMID: 1317725), resulting in an in-frame deletion of Val868 to Val909 (3.9% of the protein; PM4). It occurs at a low frequency in gnomADv2.1.1 with a MAF of 0.00006523 in the East Asian population (PM2_supporting). At least 3 compound heterozygous probands are reported in the literature, with the other variants being Leu973AlafsTer63, Leu214Pro, and Ala777Asp (PMID: 15748238, PMID: 27696190, PMID: 29675921; PM3). In summary, based on the available evidence at this time, the c.2602-3C>G variant is classified as likely pathogenic. GT-specific criteria applied: PM2_supporting, PM3, PM4, PP4_strong. -

Glanzmann thrombasthenia 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Benign

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.30

Position offset: -3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over