chr1-22863060-G-T

Position:

chr1-22863060-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The ENST00000374630.8(EPHB2):c.835G>T(p.Ala279Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,614,160 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 2 hom. )

Consequence

EPHB2
ENST00000374630.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:2

Conservation

PhyloP100: 0.593

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EPHB2. . Gene score misZ 2.4517 (greater than the threshold 3.09). Trascript score misZ 4.1115 (greater than threshold 3.09). GenCC has associacion of gene with bleeding disorder, platelet-type, 22.

BP4

Computational evidence support a benign effect (MetaRNN=0.004200548).

BP6

Variant 1-22863060-G-T is Benign according to our data. Variant chr1-22863060-G-T is described in ClinVar as [Benign]. Clinvar id is 8533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHB2	NM_017449.5 linkuse as main transcript	c.835G>T	p.Ala279Ser	missense_variant	4/16	ENST00000374630.8	NP_059145.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHB2	ENST00000374630.8 linkuse as main transcript	c.835G>T	p.Ala279Ser	missense_variant	4/16	1	NM_017449.5	ENSP00000363761	P4	P29323-2

Frequencies

GnomAD3 genomes

AF:

0.00379

AC:

576

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00107

AC:

270

AN:

251316

Hom.:

AF XY:

0.000898

AC XY:

122

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000363

AC:

530

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000333

AC XY:

242

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0132

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.00379

AC:

577

AN:

152270

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

274

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0134

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000668

Hom.:

Bravo

AF:

0.00450

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00116

AC:

141

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Prostate cancer/brain cancer susceptibility

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0088

T;.;T;.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.92

D;D;D;D;D

MetaRNN

Benign

0.0042

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.32

.;N;N;N;.

MutationTaster

Benign

0.93

A;A;A;A;A

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.3

N;N;N;N;N

REVEL

Benign

0.029

Sift

Benign

0.39

T;T;T;T;T

Sift4G

Benign

0.62

T;T;T;T;T

Polyphen

0.0090, 0.0010

.;.;B;B;.

Vest4

0.15

MVP

0.34

MPC

0.51

ClinPred

0.019

GERP RS

3.7

Varity_R

0.20

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over