rs4612601

Variant names:

• chr1-22740551-G-A
• rs4612601
• NM_017449.5:c.61+29508G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017449.5(EPHB2):​c.61+29508G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 151,998 control chromosomes in the GnomAD database, including 22,742 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (22742 hom., cov: 32)
• Consequence: EPHB2 NM_017449.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB2	NM_017449.5	c.61+29508G>A		intron_variant	Intron 1 of 15	ENST00000374630.8	NP_059145.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB2	ENST00000374630.8	c.61+29508G>A		intron_variant	Intron 1 of 15	1	NM_017449.5	ENSP00000363761.3
EPHB2	ENST00000400191.7	c.61+29508G>A		intron_variant	Intron 1 of 16	1		ENSP00000383053.3
EPHB2	ENST00000374632.7	c.61+29508G>A		intron_variant	Intron 1 of 15	1		ENSP00000363763.3
EPHB2	ENST00000544305.5	c.61+29508G>A		intron_variant	Intron 1 of 6	1		ENSP00000444174.1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81846 AN: 151878 Hom.: 22701 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.723

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.937

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.520

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.539 AC: 81944 AN: 151998 Hom.: 22742 Cov.: 32 AF XY: 0.550 AC XY: 40835 AN XY: 74288

African (AFR) AF: 0.516 AC: 21380 AN: 41446

American (AMR) AF: 0.596 AC: 9112 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1543 AN: 3470

East Asian (EAS) AF: 0.936 AC: 4824 AN: 5152

South Asian (SAS) AF: 0.711 AC: 3428 AN: 4820

European-Finnish (FIN) AF: 0.549 AC: 5806 AN: 10570

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.500 AC: 33951 AN: 67934

Other (OTH) AF: 0.525 AC: 1108 AN: 2110

Alfa AF: 0.527 Hom.: 16293

Bravo AF: 0.540

Asia WGS AF: 0.788 AC: 2741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.10
DANN	Benign	0.55
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4612601; hg19: chr1-23067044;