dbSNP rs76826147: EPHB2:p.Lys1019Gln (chr1-22913757-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000400191.7(EPHB2):c.3055A>C(p.Lys1019Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EPHB2
ENST00000400191.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.261

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 Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

EPHB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0795497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB2	NM_017449.5 link	c.*187A>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000374630.8	NP_059145.2	P29323-2Q6NVW1Q4LE53

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPHB2	ENST00000400191.7 link	c.3055A>C	p.Lys1019Gln	missense_variant	Exon 17 of 17	1		ENSP00000383053.3	P29323-1
EPHB2	ENST00000374630.8 link	c.*187A>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_017449.5	ENSP00000363761.3	P29323-2
EPHB2	ENST00000374632.7 link	c.*187A>C		3_prime_UTR_variant	Exon 16 of 16	1		ENSP00000363763.3	P29323-3
EPHB2	ENST00000374627.1 link	c.*1154A>C		downstream_gene_variant		5		ENSP00000363758.1	B1AKC9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

43076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.00

AC:

AN:

84954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108264

Other (OTH)

AF:

0.00

AC:

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.3

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.075

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.36

M_CAP

Uncertain

0.090

MetaRNN

Benign

0.080

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.0

PhyloP100

0.26

PROVEAN

Benign

0.010

REVEL

Benign

0.15

Sift

Pathogenic

0.0

Polyphen

0.0

Vest4

0.13

MutPred

0.12

Loss of methylation at K1019 (P = 0.0152);

MVP

0.67

ClinPred

0.096

GERP RS

0.90

Varity_R

0.15

gMVP

0.046

Mutation Taster

=96/4

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over