13-106493156-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_004093.4(EFNB2):c.886G>T(p.Ala296Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: EFNB2 NM_004093.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

Genes affected

EFNB2 (HGNC:3227): (ephrin B2) This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNB class ephrin which binds to the EPHB4 and EPHA3 receptors. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EFNB2
• BP4: Computational evidence support a benign effect (MetaRNN=0.18168685).
• BS2: High AC in GnomAdExome at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFNB2	NM_004093.4	c.886G>T	p.Ala296Ser	missense_variant	5/5	ENST00000646441.1
EFNB2	NM_001372056.1	c.793G>T	p.Ala265Ser	missense_variant	4/4
EFNB2	NM_001372057.1	c.772G>T	p.Ala258Ser	missense_variant	4/4
EFNB2	XM_017020406.3	c.892G>T	p.Ala298Ser	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFNB2	ENST00000646441.1	c.886G>T	p.Ala296Ser	missense_variant	5/5		NM_004093.4	P1
	ENST00000646480.1	n.496+278C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251422 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461824 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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

Oct 06, 2021

The c.886G>T (p.A296S) alteration is located in exon 5 (coding exon 5) of the EFNB2 gene. This alteration results from a G to T substitution at nucleotide position 886, causing the alanine (A) at amino acid position 296 to be replaced by a serine (S). 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	0.072
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.070	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	-0.90	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.30	N;.
REVEL	Uncertain	0.36
Sift	Benign	0.53	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.044	B;B
Vest4		0.46
MVP		0.75
MPC		0.70
ClinPred		0.087	T
GERP RS		5.8
Varity_R		0.069
gMVP		0.43

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: rs767538286; hg19: chr13-107145504;