ITGA2B
protein-codingintegrin subunit alpha 2b, the group of CD molecules|Integrin alpha subunits|Protein phosphatase 1 regulatory subunits
Gene summary
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]
- GP2B
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008552
Submitter: ClinGen
*ITGA2B* was first reported in relation to autosomal dominant platelet-type bleeding disorder 16 in 1998 (Peyruchaud et al., 1998, PMID: 9834222). At least 5 unique variants (4 missense variants and 1 single amino acid deletion in the highly conserved GFFKR sequence of the cytoplasmic domain) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 29 probands in 10 publications (PMIDs: 29090484, 24498605, 21454453, 9834222, 31119735, 31064749, 33276370, 32581362, 34355501, 36430862). Variants in this gene segregated with disease in 27 additional family members. The mechanism for disease is thought to be heterozygous gain of function, or activating, mutations (PMIDs: 9834222, 21454453). Of note, this gene has also been implicated in autosomal recessive Glanzmann’s Thrombasthenia due to loss of function variants. This has been assessed separately. This gene-disease association is supported by its shared biochemical function (PMID: 6460044) and protein interaction with *ITG3B* (PMID: 6213621), and functional alteration in both patient (PMID: 29090484) and non-patient (PMID: 21454453) cells, indicating a defect in proplatelet formation. Additionally, a knock-in mouse model recapitulated the macrothrombocytopenia phenotype due to constuative activation (PMID: 31691484). In summary, there is definitive evidence supporting the relationship between *ITGA2B* and autosomal dominant platelet-type bleeding disorder 16. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the HT GCEP on 06/25/2021. It was reevaluated on 10/23/2023. As a result of this reevaluation 9 additional patients were identified (PMIDs: 32581362, 34355501, 36430862) and increased the classification from Moderate to Definitive (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0010119
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0031332
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0015372
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008552
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008552
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0031332
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0980724
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0100326
Submitter: ClinGen
The ITGA2B gene has been associated with the autosomal recessive condition Glanzmann Thrombasthenia, using the ClinGen Clinical Validity Framework as of 01/14/2019. This association was made using case-level data only. At least 149 variants in this gene are reported in humans, including frameshifts, splicing variants, nonsense, and functionally-characterized missense variants. Glanzmann’s Thrombasthenia is characterized by a bleeding diathesis diagnosed by an increased bleeding time, reduced platelet aggregation and lack of clot retraction. ITGA2B was first associated with this disease in humans as early as 1991 (Burk et al., PMID: 1702098). Summary of Case Level Data: 12 POINTS The association is seen in at least 11 probands in 4 publications (PMIDs: 1702098, 9473221, 20020534, 7508443). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is biallelic loss of function, with the majority of variants observed resulting in reduced or absent expression of the integrin αIIbβ3 receptor complex on the platelet surface (PMID: 2014236). Of note, this gene has also been implicated in a Glanzmann-like autosomal dominant bleeding disorder, platelet-type, 16 with the predominant observation of macrothrombocytopenia. The disease is suggested to result from activating mutations (PMIDs: 9834222, 21454453). This will be assessed separately. Summary of Experimental Data: 3.5 POINTS This gene-disease association is supported by biochemical function, protein interactions, functional alteration, and model systems. The pathological mechanism of the disease is impaired platelet aggregation due to diminished biochemical function (fibrinogen binding) of the αIIbβ3 receptor complex (PMID: 6460044). This gene encodes glycoprotein IIb, which interacts with the protein coded by ITGB3, glycoprotein IIIa, to form the αIIbβ3 receptor complex expressed on the surface of platelets and bind fibrinogen (PMID: 6213621). Functional alteration has been validated in non-patient cells, in which CHO cells expressing variant glycoprotein IIb have inhibited binding to fibrinogen (PMID: 9473221). The null mouse recapitulates the Glanzmann’s phenotype of impaired platelet aggregation (PMID: 16103235). Summary Statement DEFINITIVE In summary, ITGA2B is definitively associated with autosomal recessive Glanzmann’s Thrombasthenia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0008552
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0010119
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008552
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals with Bleeding disorder, platelet-type, 16 may have mild disease, but awareness may allow prompt diagnosis, allowing preventive measures and rapid treatment of bleedin episodes; Individuals with Glanzmann thrombasthenia can have severe bleeding diatheses, and preventive measures as well as rapid treatment (which can include local measures as well as platelet transfusions, recombinant activated factor VII, and octreotide for GI bleeding) can be beneficial; Precipitating factors should be avoided
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ITGA2B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000419.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 1 | 14 | 122 | 5 | 143 |
| missense | 25 | 57 | 384 | 9 | 7 | 482 |
| nonsense | 38 | 11 | 2 | 51 | ||
| start loss | 0 | |||||
| frameshift | 65 | 19 | 6 | 90 | ||
| splice donor/acceptor (+/-2bp) | 27 | 11 | 3 | 41 | ||
| Total | 156 | 99 | 409 | 131 | 12 | 807 |
Highest pathogenic variant AF is 0.00006445232
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000410.2 | 30 | MANE Select | |
| Ensembl | ENSP00000262407.5 | 30 | MANE Select | |
| Ensembl | ENSP00000467269.1 | 3 | Standard | |
| Ensembl | ENSP00000498119.1 | 25 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| itga2b | Danio rerio | Structure: thrombocyte Quality: decreased functionality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Platelet activation - Homo sapiens (human)
- ECM-receptor interaction - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- Dilated cardiomyopathy (DCM) - Homo sapiens (human)
Biological Process
- platelet degranulation
- positive regulation of leukocyte migration
- cell-matrix adhesion
- integrin-mediated signaling pathway
- extracellular matrix organization
Molecular Function
- protein binding
- identical protein binding
- metal ion binding
- extracellular matrix binding
- fibrinogen binding
Cellular Component
- plasma membrane
- focal adhesion
- integrin complex
- external side of plasma membrane
- cell surface
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262407
- Coding exons
- 30
- Length
- 17326
- Individuals with no LoFs
- 125666
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 82
- Defined
- 125748
- p
- 0.000326
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.23 | 512 | 597 | 0.858 | 0.0000357 | 6611 |
| Missense (PolyPhen) | 175 | 216.56 | 0.80807 | 2402 | ||
| Synonymous | 1.14 | 235 | 258 | 0.910 | 0.0000165 | 2157 |
| Loss of Function | 3.14 | 36 | 62.9 | 0.572 | 0.00000334 | 643 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00044 | 0.00043 | rare |
| Latino/Admixed American | 0.00041 | 0.00040 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00065 | 0.00065 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.00066 | 0.00065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha- IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface.;
- Disease
- DISEASE: Glanzmann thrombasthenia (GT) [MIM:273800]: A common inherited disease of platelet aggregation. It is characterized by mucocutaneous bleeding of mild-to-moderate severity. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb-IIIa complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the GPIIb-IIIa complex at reduced levels, have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. {ECO:0000269|PubMed:10607701, ECO:0000269|PubMed:11798398, ECO:0000269|PubMed:12083483, ECO:0000269|PubMed:12181054, ECO:0000269|PubMed:12424194, ECO:0000269|PubMed:12506038, ECO:0000269|PubMed:15099289, ECO:0000269|PubMed:15219201, ECO:0000269|PubMed:17018384, ECO:0000269|PubMed:20020534, ECO:0000269|PubMed:7508443, ECO:0000269|PubMed:7706461, ECO:0000269|PubMed:8282784, ECO:0000269|PubMed:8704171, ECO:0000269|PubMed:9215749, ECO:0000269|PubMed:9473221, ECO:0000269|PubMed:9722314, ECO:0000269|PubMed:9734640, ECO:0000269|PubMed:9763559, ECO:0000269|PubMed:9920835}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bleeding disorder, platelet-type 16 (BDPLT16) [MIM:187800]: An autosomal dominant form of congenital macrothrombocytopenia associated with platelet anisocytosis. It is a disorder of platelet production. Affected individuals may have no or only mildly increased bleeding tendency. In vitro studies show mild platelet functional abnormalities. {ECO:0000269|PubMed:21454453, ECO:0000269|PubMed:9834222}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.107
Intolerance Scores
- LoFtool
- 0.500
- RVIS EVS
- -0.33
- RVIS percentile EVS
- 30.9
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.769
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | High | Medium | High |