1-22784658-G-A

Position:

• chr1-22784658-G-A

Variant summary

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

The NM_017449.5(EPHB2):​c.393G>A​(p.Met131Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M131V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EPHB2 NM_017449.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

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.393G>A	p.Met131Ile	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.393G>A	p.Met131Ile	missense_variant	3/16	1	NM_017449.5	ENSP00000363761.3
EPHB2	ENST00000374627.1	c.375G>A	p.Met125Ile	missense_variant	3/15	5		ENSP00000363758.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251272 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

May 03, 2023

The c.393G>A (p.M131I) alteration is located in exon 3 (coding exon 3) of the EPHB2 gene. This alteration results from a G to A substitution at nucleotide position 393, causing the methionine (M) at amino acid position 131 to be replaced by an isoleucine (I). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T;.;T;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.0040	T
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.3	.;M;M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.046	D;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.58, 0.52	.;.;P;P;.
Vest4		0.80
MutPred		0.49		Loss of disorder (P = 0.3614);Loss of disorder (P = 0.3614);Loss of disorder (P = 0.3614);Loss of disorder (P = 0.3614);.;
MVP		0.42
MPC		0.79
ClinPred		0.43	T
GERP RS		5.4
Varity_R		0.48
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs746387783; hg19: chr1-23111151;