17-44375719-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 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
NM_000419.5 splice_region, intron

Scores

Splicing: ADA: 0.9972

Clinical Significance

Likely pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 0.978

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 16
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Glanzmann thrombasthenia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Glanzmann's thrombasthenia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
Glanzmann thrombasthenia 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ITGA2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000419.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.2602-3C>G		splice_region intron	N/A	NP_000410.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.2602-3C>G	splice_region intron	N/A	ENSP00000262407.5
ITGA2B	ENST00000648408.1		c.2032-3C>G	splice_region intron	N/A	ENSP00000498119.1
ITGA2B	ENST00000587295.5	TSL:3	c.252+114C>G	intron	N/A	ENSP00000467269.1

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

GnomAD2 exomes

AF:

0.00000551

AC:

AN:

181340

AF XY:

0.0000103

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 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

African (AFR)

AF:

0.00

AC:

AN:

32870

American (AMR)

AF:

0.00

AC:

AN:

37330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25340

East Asian (EAS)

AF:

0.000158

AC:

AN:

38030

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81720

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090494

Other (OTH)

AF:

0.00

AC:

AN:

58852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Pathogenic:2

Sep 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.007%). For these reasons, this variant has been classified as Pathogenic. 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). 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 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.

Sep 07, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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

Jun 15, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.51

PhyloP100

0.98

PromoterAI

0.021

Neutral

(source)

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over