rs28936395

chr1-22906853-G-Achr1-22906853-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_017449.5(EPHB2):c.2032G>A(p.Asp678Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,614,172 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D678E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (31 hom.)
• Consequence: EPHB2 NM_017449.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EPHB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.02323693).
• BP6: Variant 1-22906853-G-A is Benign according to our data. Variant chr1-22906853-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 8534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHB2	NM_017449.5	c.2032G>A	p.Asp678Asn	missense_variant	11/16	ENST00000374630.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHB2	ENST00000374630.8	c.2032G>A	p.Asp678Asn	missense_variant	11/16	1	NM_017449.5	P4
EPHB2	ENST00000400191.7	c.2032G>A	p.Asp678Asn	missense_variant	11/17	1
EPHB2	ENST00000374632.7	c.2035G>A	p.Asp679Asn	missense_variant	11/16	1		A1
EPHB2	ENST00000374627.1	c.2017G>A	p.Asp673Asn	missense_variant	11/15	5

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00554

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00347 AC: 872 AN: 251398 Hom.: 0 AF XY: 0.00343 AC XY: 466 AN XY: 135898

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00573

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00558 AC: 8163 AN: 1461882 Hom.: 31 Cov.: 31 AF XY: 0.00535 AC XY: 3888 AN XY: 727246

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00664

Gnomad4 OTH exome AF: 0.00531

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00295 AC XY: 220 AN XY: 74460

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00554

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00388 Hom.: 1

Bravo AF: 0.00359

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00342 AC: 415

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00551

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Prostate cancer/brain cancer susceptibility Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

EPHB2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.41	N;N;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.030	D;D;D;D
Sift4G	Benign	0.10	T;T;T;T
Polyphen		1.0, 0.94	.;D;P;.
Vest4		0.61
MVP		0.76
MPC		1.4
ClinPred		0.039	T
GERP RS		5.4
Varity_R		0.47
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs28936395; hg19: chr1-23233346; COSMIC: COSV65862469;