NM_000419.5:c.2621T>G

Variant names:

• chr17-44375697-A-C
• rs5911
• NM_000419.5:c.2621T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP2 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The ITGA2B c.2621T>G (p.Ile874Ser) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis with several other Glanzmann thrombasthenia variants, including the pathogenic Tyr471Ter and c.1440-13_1440-1del ITGA2B variants and the Pro189Ser ITGB3 variant (PMID:25728920). It is present in gnomAD at an overall allele frequency of 0.39177 (and 0.43954 in the non-Finnish European population). Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.055. In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BP2, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115831/MONDO:0010119/011

• Frequency:
  • Genomes: 𝑓 0.39 (11564 hom., cov: 32)
  • Exomes 𝑓: 0.38 (103365 hom.)
• Consequence: ITGA2B NM_000419.5 missense
• Clinical Significance: Benign reviewed by expert panel B:7 O:1
• Conservation: PhyloP100: 1.20
• Publications: 65 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Glanzmann thrombasthenia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann's thrombasthenia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Glanzmann thrombasthenia 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	NM_000419.5	MANE Select	c.2621T>G	p.Ile874Ser	missense	Exon 26 of 30	NP_000410.2	P08514-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.2621T>G	p.Ile874Ser	missense	Exon 26 of 30	ENSP00000262407.5	P08514-1
	ITGA2B	ENST00000901307.1		c.2621T>G	p.Ile874Ser	missense	Exon 26 of 29	ENSP00000571366.1
	ITGA2B	ENST00000949677.1		c.2621T>G	p.Ile874Ser	missense	Exon 26 of 29	ENSP00000619736.1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59117 AN: 151816 Hom.: 11571 Cov.: 32

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.362

GnomAD2 exomes AF: 0.390 AC: 80860 AN: 207394 AF XY: 0.386

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.379

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.379 AC: 544794 AN: 1438576 Hom.: 103365 Cov.: 44 AF XY: 0.377 AC XY: 268972 AN XY: 713728

African (AFR) AF: 0.375 AC: 12483 AN: 33278

American (AMR) AF: 0.372 AC: 14766 AN: 39732

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 10878 AN: 25560

East Asian (EAS) AF: 0.428 AC: 16648 AN: 38926

South Asian (SAS) AF: 0.346 AC: 28911 AN: 83490

European-Finnish (FIN) AF: 0.432 AC: 22209 AN: 51440

Middle Eastern (MID) AF: 0.353 AC: 2019 AN: 5724

European-Non Finnish (NFE) AF: 0.376 AC: 414121 AN: 1100854

Other (OTH) AF: 0.382 AC: 22759 AN: 59572

GnomAD4 genome AF: 0.389 AC: 59125 AN: 151934 Hom.: 11564 Cov.: 32 AF XY: 0.388 AC XY: 28837 AN XY: 74248

African (AFR) AF: 0.394 AC: 16334 AN: 41464

American (AMR) AF: 0.349 AC: 5332 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1515 AN: 3472

East Asian (EAS) AF: 0.445 AC: 2288 AN: 5138

South Asian (SAS) AF: 0.352 AC: 1694 AN: 4812

European-Finnish (FIN) AF: 0.435 AC: 4598 AN: 10566

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26136 AN: 67910

Other (OTH) AF: 0.359 AC: 756 AN: 2106

Alfa AF: 0.381 Hom.: 6522

Bravo AF: 0.382

TwinsUK AF: 0.370 AC: 1372

ALSPAC AF: 0.363 AC: 1399

ESP6500AA AF: 0.390 AC: 1714

ESP6500EA AF: 0.374 AC: 3211

ExAC AF: 0.359 AC: 42729

Asia WGS AF: 0.402 AC: 1404 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Glanzmann thrombasthenia (3)
-	-	2	not specified (2)
-	-	1	Glanzmann thrombasthenia 1 (1)
-	-	1	not provided (1)
-	-	-	BAK PLATELET-SPECIFIC ANTIGEN (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.055
Sift	Benign	0.21	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.032
MPC		0.42
ClinPred		0.0069	T
GERP RS		3.4
PromoterAI		0.012	Neutral
Varity_R		0.049
gMVP		0.32
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs5911; hg19: chr17-42453065; COSMIC: COSV52233480; COSMIC: COSV52233480;