rs12133964

Variant names:

• chr1-22808522-G-A
• rs12133964
• NM_017449.5:c.811+23446G>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.811+23446G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,194 control chromosomes in the GnomAD database, including 2,971 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 0.19 (2971 hom., cov: 33)
• Consequence: EPHB2 NM_017449.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.868
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017449.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB2	NM_017449.5	MANE Select	c.811+23446G>A		intron	N/A	NP_059145.2
	EPHB2	NM_001309193.2		c.811+23446G>A		intron	N/A	NP_001296122.1
	EPHB2	NM_004442.7		c.811+23446G>A		intron	N/A	NP_004433.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB2	ENST00000374630.8	TSL:1 MANE Select	c.811+23446G>A		intron	N/A	ENSP00000363761.3
	EPHB2	ENST00000400191.7	TSL:1	c.811+23446G>A		intron	N/A	ENSP00000383053.3
	EPHB2	ENST00000374632.7	TSL:1	c.811+23446G>A		intron	N/A	ENSP00000363763.3

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29624 AN: 152076 Hom.: 2975 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.183

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

GnomAD4 genome AF: 0.195 AC: 29616 AN: 152194 Hom.: 2971 Cov.: 33 AF XY: 0.196 AC XY: 14604 AN XY: 74404

African (AFR) AF: 0.172 AC: 7162 AN: 41530

American (AMR) AF: 0.232 AC: 3551 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 550 AN: 3470

East Asian (EAS) AF: 0.185 AC: 957 AN: 5174

South Asian (SAS) AF: 0.328 AC: 1576 AN: 4806

European-Finnish (FIN) AF: 0.163 AC: 1724 AN: 10602

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13471 AN: 67994

Other (OTH) AF: 0.180 AC: 381 AN: 2112

Alfa AF: 0.191 Hom.: 374

Bravo AF: 0.194

Asia WGS AF: 0.236 AC: 823 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.6
DANN	Benign	0.64
PhyloP100		0.87
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: rs12133964; hg19: chr1-23135015;