1-22913757-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_ModerateBS1_SupportingBS2

The ENST00000400191.7(EPHB2):c.3055A>T(p.Lys1019*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,606,538 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.011 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 37 hom. )

Consequence

EPHB2
ENST00000400191.7 stop_gained

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 0.261

Publications

17 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0357 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1684/152300) while in subpopulation AFR AF = 0.0379 (1574/41560). AF 95% confidence interval is 0.0363. There are 35 homozygotes in GnomAd4. There are 796 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 35 Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000400191.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPHB2	NM_017449.5	MANE Select	c.*187A>T		3_prime_UTR	Exon 16 of 16	NP_059145.2
EPHB2	NM_001309193.2		c.3055A>T	p.Lys1019*	stop_gained	Exon 17 of 17	NP_001296122.1
EPHB2	NM_004442.7		c.*187A>T		3_prime_UTR	Exon 16 of 16	NP_004433.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPHB2	ENST00000400191.7	TSL:1	c.3055A>T	p.Lys1019*	stop_gained	Exon 17 of 17	ENSP00000383053.3
EPHB2	ENST00000374630.8	TSL:1 MANE Select	c.*187A>T		3_prime_UTR	Exon 16 of 16	ENSP00000363761.3
EPHB2	ENST00000374632.7	TSL:1	c.*187A>T		3_prime_UTR	Exon 16 of 16	ENSP00000363763.3

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1675

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0378

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00288

AC:

679

AN:

235858

AF XY:

0.00206

show subpopulations

Gnomad AFR exome

AF:

0.0387

Gnomad AMR exome

AF:

0.00218

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00254

GnomAD4 exome

AF:

0.00123

AC:

1794

AN:

1454238

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

767

AN XY:

722618

show subpopulations

African (AFR)

AF:

0.0413

AC:

1377

AN:

33356

American (AMR)

AF:

0.00239

AC:

103

AN:

43074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25982

East Asian (EAS)

AF:

0.00

AC:

AN:

39596

South Asian (SAS)

AF:

0.0000824

AC:

AN:

84954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53072

Middle Eastern (MID)

AF:

0.00521

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000803

AC:

AN:

1108264

Other (OTH)

AF:

0.00312

AC:

188

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0111

AC:

1684

AN:

152300

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

796

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0379

AC:

1574

AN:

41560

American (AMR)

AF:

0.00562

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68028

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

164

245

327

409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000628

Hom.:

Bravo

AF:

0.0127

ESP6500AA

AF:

0.0399

AC:

125

ESP6500EA

AF:

0.000279

AC:

ExAC

AF:

0.00335

AC:

406

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Prostate cancer/brain cancer susceptibility

Other:1

Jun 01, 2006

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.6

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.41

PhyloP100

0.26

Vest4

0.44

GERP RS

0.90

Mutation Taster

=176/24

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over