1-16125229-CCA-C
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_004431.5(EPHA2):c.2915_2916delTG(p.Val972fs) 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
NM_004431.5 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00546 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| EPHA2 | NM_004431.5 | c.2915_2916delTG | p.Val972fs | frameshift_variant | 17/17 | ENST00000358432.8 | NP_004422.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cataract 6 multiple types Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2019 | 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. 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. 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). - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at