1-16132227-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_004431.5(EPHA2):c.2162G>A(p.Arg721Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,614,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004431.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EPHA2 | NM_004431.5 | c.2162G>A | p.Arg721Gln | missense_variant | Exon 13 of 17 | ENST00000358432.8 | NP_004422.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000690 AC: 105AN: 152214Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000736 AC: 185AN: 251218Hom.: 0 AF XY: 0.000560 AC XY: 76AN XY: 135818
GnomAD4 exome AF: 0.00125 AC: 1830AN: 1461830Hom.: 0 Cov.: 33 AF XY: 0.00120 AC XY: 871AN XY: 727220
GnomAD4 genome AF: 0.000689 AC: 105AN: 152332Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56AN XY: 74484
ClinVar
Submissions by phenotype
Cataract 6 multiple types Uncertain:1Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 721 of the EPHA2 protein (p.Arg721Gln). This variant is present in population databases (rs116506614, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with cortical cataract (PMID: 19649315, 29267365). ClinVar contains an entry for this variant (Variation ID: 13262). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EPHA2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EPHA2 function (PMID: 19649315). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cataract 6, age-related cortical Pathogenic:1
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not specified Uncertain:1
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Meniere disease Uncertain:1
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EPHA2-related disorder Uncertain:1
The EPHA2 c.2162G>A variant is predicted to result in the amino acid substitution p.Arg721Gln. This variant was previously reported in individuals affected by late-onset cataract in one family; however, several affected family members did not harbor this variant (Jun et al. 2009. PubMed ID: 19649315). In vitro analysis of the p.Arg721Gln variant demonstrated an increase in the basal activation of EPHA2 kinase and subsequently increased basal ERK1/2 activities. In mouse models harboring the p.Arg721Gln variant (referred to as Epha2-Q722 in the mouse), cataract formation was not observed; however, differences in gene expression in the lens was noted (Zhou et al. 2021. PubMed ID: 34685586). This variant is reported in 0.13% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org), which is likely too frequent to be associated with a highly penetrant cause of disease. In ClinVar, this variant has conflicting interpretations ranging from likely benign to pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/13262/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at