rs137852917
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_005670.4(EPM2A):c.835G>T(p.Gly279Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 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. G279S) 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPM2A | NM_005670.4 | c.835G>T | p.Gly279Cys | missense_variant | 4/4 | ENST00000367519.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPM2A | ENST00000367519.9 | c.835G>T | p.Gly279Cys | missense_variant | 4/4 | 1 | NM_005670.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 249864Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135196
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Progressive myoclonic epilepsy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2019 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with late-onset Lafora disease in a family (PMID: 25246353). This variant is present in population databases (rs137852917, ExAC 0.02%). This sequence change replaces glycine with cysteine at codon 279 of the EPM2A protein (p.Gly279Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at