rs104893955
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_005670.4(EPM2A):c.94T>G(p.Trp32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,243,234 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W32R) has been classified as Uncertain significance.
Frequency
Consequence
NM_005670.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPM2A | NM_005670.4 | c.94T>G | p.Trp32Gly | missense_variant | 1/4 | ENST00000367519.9 | |
EPM2A-DT | NR_038246.1 | n.52+485A>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPM2A | ENST00000367519.9 | c.94T>G | p.Trp32Gly | missense_variant | 1/4 | 1 | NM_005670.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000668 AC: 1AN: 149622Hom.: 0 Cov.: 33
GnomAD4 exome AF: 9.14e-7 AC: 1AN: 1093504Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 527836
GnomAD4 genome ? AF: 0.00000668 AC: 1AN: 149730Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1AN XY: 73070
ClinVar
Submissions by phenotype
Lafora disease Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 25, 2002 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2023 | Multiple published functional studies demonstrate a damaging effect, as W32G alters protein stability and phosphatase activity, damaging the intracellular glycogen complex and leading to mis-targeting of laforin (Ganesh et al., 2002; Wang et al., 2002; Wang et al., 2004; Srikumar et al., 2014; Meekins et al., 2015; Raththagala et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14532330, 14706656, 18029386, 18040046, 25544560, 24770803, 15541350, 26231210, 10932264, 22669944, 34755096, 33084218, 34117373, 12019207, 28934672, 31227012, 11739371) - |
Progressive myoclonic epilepsy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 32 of the EPM2A protein (p.Trp32Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with EPM2A-related conditions (PMID: 10932264). ClinVar contains an entry for this variant (Variation ID: 3107). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects EPM2A function (PMID: 11739371, 12019207, 14532330). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at