chr6-145627577-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_005670.4(EPM2A):c.835G>A(p.Gly279Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G279C) has been classified as Pathogenic.
Frequency
Consequence
NM_005670.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPM2A | NM_005670.4 | c.835G>A | p.Gly279Ser | missense_variant | 4/4 | ENST00000367519.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPM2A | ENST00000367519.9 | c.835G>A | p.Gly279Ser | missense_variant | 4/4 | 1 | NM_005670.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249864Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135196
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Lafora disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2005 | - - |
not provided Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 24, 2017 | - - |
Progressive myoclonic epilepsy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 25, 2023 | This missense change has been observed in individual(s) with Lafora disease (PMID: 9771710, 33773408). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly279 amino acid residue in EPM2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25246353). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects EPM2A function (PMID: 12019207, 14532330). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EPM2A protein function. ClinVar contains an entry for this variant (Variation ID: 3099). This variant is present in population databases (rs137852917, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 279 of the EPM2A protein (p.Gly279Ser). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at