EPHB2
protein-codingEPH receptor B2, the group of Sterile alpha motif domain containing|EPH receptors|MicroRNA protein coding host genes
Gene summary
This gene encodes a member of the Eph receptor family of receptor tyrosine kinase transmembrane glycoproteins. These receptors are composed of an N-terminal glycosylated ligand-binding domain, a transmembrane region and an intracellular kinase domain. They bind ligands called ephrins and are involved in diverse cellular processes including motility, division, and differentiation. A distinguishing characteristic of Eph-ephrin signaling is that both receptors and ligands are competent to transduce a signaling cascade, resulting in bidirectional signaling. This protein belongs to a subgroup of the Eph receptors called EphB. Proteins of this subgroup are distinguished from other members of the family by sequence homology and preferential binding affinity for membrane-bound ephrin-B ligands. Allelic variants are associated with prostate and brain cancer susceptibility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]
- DRT
- ERK
- EPHT3
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~210.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0032765
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0032765
Submitter: ClinGen
In 2018, the EPHB2 gene was first reported in association with a recessive bleeding disorder characterized by excessive spontaneous subcutaneous bleeding, heavy bleeding after minor wounds, chronic gastrointestinal bleeding leading to anemia, and a mild decrease in platelet count observed later in life (Berrou E, et al., 2018, PMID: 30213874). Platelet function tests revealed decreased responses to various agonists except ristocetin, with normal ATP/ADP content and dense granule numbers. Both the patient and the affected sibling, who are homozygous for the NM_017449.5 :c.2233C>T (p.Arg745Cys) variant in the tyrosine kinase domain of EPHB2, displayed significant defects in platelet function with similar abnormalities (PMID: 30213874). Further experimental evidence supports the pathogenicity of this variant, indicating that the p.R745C variant in EPHB2 causes significant platelet dysfunction, including structural abnormalities, reduced aggregation, impaired activation, and enhanced clustering under stimulated conditions, suggesting disrupted signaling pathways. The EPHB2-R745C mutation impairs autophosphorylation by 50% without affecting clustering behavior, disrupting early cell activation steps independently of cell-cell contact (PMID: 30213874). Additionally, there is evidence of EphB2 interaction with ITGB3 in platelet function, as well as EphB2 signaling's role in thrombus stability (PMID: 25370417). EPHB2 truncation studies in mice (PMID: 25370417) and the expression of EPHB2 in platelets provide further support (PMID: 30213874). For the genetic evidence, only one consanguineous family with two similarly affected individuals has been identified. Currently, both the genetic and experimental evidence suggest a borderline classification between limited and moderate. However, due to the limited genetic data, we will maintain the final classification as limited until more genetic evidence becomes available. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP 10
Inheritance Pattern: AR
Disease ID:MONDO:0032765
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals have been described with spontaneous subcutaneous bleeding as well as excessive bleeding after minor injuries, and awareness may allow preventative measures to avoid sequelae, as well as other management options (e.g., iron treatment has been described in one patient)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to EPHB2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017449.5. 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 | 3 | 36 | 7 | 46 | ||
| missense | 1 | 93 | 6 | 1 | 101 | |
| nonsense | 1 | 1 | 2 | |||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 2 | 0 | 101 | 42 | 8 | 153 |
Highest pathogenic variant AF is 0.0000043366695
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_059145.2 | 16 | MANE Select | |
| Ensembl | ENSP00000363761.3 | 16 | MANE Select | |
| RefSeq | NP_001296121.1 | 14 | Standard | |
| RefSeq | NP_001296122.1 | 17 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Axon guidance - Homo sapiens (human)
- Regulation of Microtubule Cytoskeleton
- NLR Proteins
- Transcriptional activation by NRF2
- Developmental Biology
Biological Process
- angiogenesis
- urogenital system development
- negative regulation of protein phosphorylation
- transmembrane receptor protein tyrosine kinase signaling pathway
- nervous system development
Molecular Function
- amyloid-beta binding
- protein tyrosine kinase activity
- transmembrane receptor protein tyrosine kinase activity
- transmembrane-ephrin receptor activity
- signaling receptor binding
Cellular Component
- extracellular region
- nucleus
- cytosol
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374632
- Coding exons
- 16
- Length
- 204487
- Individuals with no LoFs
- 125728
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 20
- Defined
- 125748
- p
- 0.0000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.45 | 465 | 639 | 0.727 | 0.0000453 | 6501 |
| Missense (PolyPhen) | 154 | 254.92 | 0.60412 | 2558 | ||
| Synonymous | 0.0652 | 267 | 268 | 0.995 | 0.0000209 | 1948 |
| Loss of Function | 5.59 | 3 | 42.2 | 0.0710 | 0.00000202 | 479 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000055 | 0.000054 | rare |
| Finnish | 0.00051 | 0.00051 | rare |
| European (Non-Finnish) | 0.000044 | 0.000044 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Functions in axon guidance during development. Involved in the guidance of commissural axons, that form a major interhemispheric connection between the 2 temporal lobes of the cerebral cortex. Also involved in guidance of contralateral inner ear efferent growth cones at the midline and of retinal ganglion cell axons to the optic disk. In addition to axon guidance, also regulates dendritic spines development and maturation and stimulates the formation of excitatory synapses. Upon activation by EFNB1, abolishes the ARHGEF15-mediated negative regulation on excitatory synapse formation. Controls other aspects of development including angiogenesis, palate development and in inner ear development through regulation of endolymph production. Forward and reverse signaling through the EFNB2/EPHB2 complex regulate movement and adhesion of cells that tubularize the urethra and septate the cloaca. May function as a tumor suppressor. {ECO:0000269|PubMed:15300251}.;
Recessive Scores
- pRec
- 0.580
Intolerance Scores
- LoFtool
- 0.112
- RVIS EVS
- -1.46
- RVIS percentile EVS
- 3.86
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.535
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |