Human Gene Module / Chromosome 1 / EPHB2

EPHB2EPH receptor B2

Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
4 / 4
Rare Variants / Common Variants
9 / 0
EPHB2, CAPB,  DRT,  EK5,  EPHT3,  ERK,  Hek5,  PCBC,  Tyro5
Associated Syndromes
Genetic Category
Rare Single Gene Mutation
Chromosome Band
Associated Disorders
Relevance to Autism

Two de novo variants (one nonsense, one missense) in the EPHB2 gene were identified in separate next-generation sequencing reports using ASD probands (Sanders et al., 2012; Kong et al., 2012).

Molecular Function

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.

Reports related to EPHB2 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
2 Support Rate of de novo mutations and the importance of father's age to disease risk. Kong A , et al. (2012) Yes -
3 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
4 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>A p.Gly900Ser missense_variant De novo - - 22914163 Kong A , et al. (2012)
c.2572C>T p.Gln858Ter stop_gained De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.3013C>T p.Arg1005Ter stop_gained Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.668G>A p.Arg223Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2531G>A p.Arg844Gln missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2731G>A p.Asp911Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2437G>A p.Gly813Ser missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.1058G>A p.Arg353Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2405G>A p.Arg802Gln missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score

Minimal Evidence



Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.


Initial score established: 4.5



Krishnan Probability Score

Score 0.60789314363908

Ranking 298/25841 scored genes

[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at
ExAC Score

Score 0.99994863523136

Ranking 588/18225 scored genes

[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.72292346645744

Ranking 1317/18665 scored genes

[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see
Larsen Cumulative Evidence Score

Score 10

Ranking 184/461 scored genes

[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.23853941854784

Ranking 3642/20870 scored genes

[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with EPHB2(1 CNVs)
1p36.12 9 Deletion-Duplication 18  /  42
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