NM_017449.5:c.344A>G

Variant names:

• chr1-22784609-A-G
• rs1557672162
• NM_017449.5:c.344A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017449.5(EPHB2):​c.344A>G​(p.Tyr115Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EPHB2 NM_017449.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30
• Publications: 0 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, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB2	NM_017449.5	MANE Select	c.344A>G	p.Tyr115Cys	missense	Exon 3 of 16	NP_059145.2	P29323-2
	EPHB2	NM_001309193.2		c.344A>G	p.Tyr115Cys	missense	Exon 3 of 17	NP_001296122.1	P29323-1
	EPHB2	NM_004442.7		c.344A>G	p.Tyr115Cys	missense	Exon 3 of 16	NP_004433.2	Q6NVW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHB2	ENST00000374630.8	TSL:1 MANE Select	c.344A>G	p.Tyr115Cys	missense	Exon 3 of 16	ENSP00000363761.3	P29323-2
	EPHB2	ENST00000400191.7	TSL:1	c.344A>G	p.Tyr115Cys	missense	Exon 3 of 17	ENSP00000383053.3	P29323-1
	EPHB2	ENST00000374632.7	TSL:1	c.344A>G	p.Tyr115Cys	missense	Exon 3 of 16	ENSP00000363763.3	P29323-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.88		Loss of phosphorylation at Y115 (P = 0.0631)
MVP		0.72
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.84
Mutation Taster		=12/88	disease causing

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: rs1557672162; hg19: chr1-23111102;