1-22784837-G-C

Variant names:

• chr1-22784837-G-C
• NM_017449.5:c.572G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017449.5(EPHB2):​c.572G>C​(p.Arg191Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R191H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPHB2 NM_017449.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.87

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB2	NM_017449.5	c.572G>C	p.Arg191Pro	missense_variant	Exon 3 of 16	ENST00000374630.8	NP_059145.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB2	ENST00000374630.8	c.572G>C	p.Arg191Pro	missense_variant	Exon 3 of 16	1	NM_017449.5	ENSP00000363761.3
EPHB2	ENST00000374627.1	c.554G>C	p.Arg185Pro	missense_variant	Exon 3 of 15	5		ENSP00000363758.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;T;.;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.2	.;M;M;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.3	D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0, 0.99	.;.;D;D;.
Vest4		0.90
MutPred		0.86		Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);.;
MVP		0.78
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.95

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: chr1-23111330;