1-22784938-A-G

Position:

• chr1-22784938-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_017449.5(EPHB2):​c.673A>G​(p.Ser225Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPHB2 NM_017449.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EPHB2. . Gene score misZ 2.4517 (greater than the threshold 3.09). Trascript score misZ 4.1115 (greater than threshold 3.09). GenCC has associacion of gene with bleeding disorder, platelet-type, 22.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHB2	NM_017449.5	c.673A>G	p.Ser225Gly	missense_variant	3/16	ENST00000374630.8	NP_059145.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHB2	ENST00000374630.8	c.673A>G	p.Ser225Gly	missense_variant	3/16	1	NM_017449.5	ENSP00000363761	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.673A>G (p.S225G) alteration is located in exon 3 (coding exon 3) of the EPHB2 gene. This alteration results from a A to G substitution at nucleotide position 673, causing the serine (S) at amino acid position 225 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;T;.;T
Eigen	Benign	0.066
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.46	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	.;L;L;L;.
MutationTaster	Benign	0.99	N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D;D;D;D;N
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.030	D;T;T;T;T
Polyphen		0.023, 0.016	.;.;B;B;.
Vest4		0.38
MutPred		0.38		Loss of phosphorylation at S225 (P = 0.0554);Loss of phosphorylation at S225 (P = 0.0554);Loss of phosphorylation at S225 (P = 0.0554);Loss of phosphorylation at S225 (P = 0.0554);.;
MVP		0.78
MPC		0.53
ClinPred		0.78	D
GERP RS		5.1
Varity_R		0.39
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-23111431;