1-16125229-CCA-C

Position:

• chr1-16125229-CCA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004431.5(EPHA2):​c.2915_2916del​(p.Val972GlyfsTer40) variant causes a frameshift 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPHA2 NM_004431.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.34

Genes affected

EPHA2 (HGNC:3386): (EPH receptor A2) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Mutations in this gene are the cause of certain genetically-related cataract disorders.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon NOT found. This looks like a Nonstop Mediated Decay case. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-16125229-CCA-C is Pathogenic according to our data. Variant chr1-16125229-CCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 849920.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPHA2	NM_004431.5	c.2915_2916del	p.Val972GlyfsTer40	frameshift_variant	17/17	ENST00000358432.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPHA2	ENST00000358432.8	c.2915_2916del	p.Val972GlyfsTer40	frameshift_variant	17/17	1	NM_004431.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 6 multiple types Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2019	For these reasons, this variant has been classified as Pathogenic. This variant results in an extension of the EPHA2 protein. Other variant(s) that result in a similarly extended protein product (p.Ile976Hisfs*37) have been determined to be pathogenic (PMID: 24940039). This suggests that these extensions are likely to be causative of disease. This variant has been reported to affect EPHA2 protein function (PMID: 22570727, 26900323). This variant has been observed in individual(s) with autosomal dominant congenital cataracts (PMID: 19306328, Invitae). This variant is also known as c.2915_2916delTG (p.V972GfsX39) in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the EPHA2 gene (p.Val972Glyfs*40). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acids of the EPHA2 protein and extend the protein by an additional 34 amino acids. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -

Computational scores

Source: dbNSFP v4.3

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: rs2024441691; hg19: chr1-16451724;