Genetic Variant EPHB2:p.Arg171Pro (chr1-22784777-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_017449.5(EPHB2):c.512G>C(p.Arg171Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R171H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

EPHB2
NM_017449.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.25

Publications

0 publications found

Variant links:

Genes affected

EPHB2 (HGNC:3393): (EPH receptor B2) 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]

EPHB2 Gene-Disease associations (from GenCC):

bleeding disorder, platelet-type, 22
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

EPHB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017449.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPHB2	NM_017449.5	MANE Select	c.512G>C	p.Arg171Pro	missense	Exon 3 of 16	NP_059145.2	P29323-2
EPHB2	NM_001309193.2		c.512G>C	p.Arg171Pro	missense	Exon 3 of 17	NP_001296122.1	P29323-1
EPHB2	NM_004442.7		c.512G>C	p.Arg171Pro	missense	Exon 3 of 16	NP_004433.2	Q6NVW1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPHB2	ENST00000374630.8	TSL:1 MANE Select	c.512G>C	p.Arg171Pro	missense	Exon 3 of 16	ENSP00000363761.3	P29323-2
EPHB2	ENST00000400191.7	TSL:1	c.512G>C	p.Arg171Pro	missense	Exon 3 of 17	ENSP00000383053.3	P29323-1
EPHB2	ENST00000374632.7	TSL:1	c.512G>C	p.Arg171Pro	missense	Exon 3 of 16	ENSP00000363763.3	P29323-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0071

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

PhyloP100

4.2

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.27

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.94

Vest4

0.80

MutPred

0.76

Loss of methylation at R171 (P = 0.0469)

MVP

0.71

MPC

1.3

ClinPred

1.0

GERP RS

5.3

Varity_R

0.92

gMVP

0.83

Mutation Taster

=36/64

disease causing

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over