rs796052430
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000367519.9(EPM2A):āc.446T>Cā(p.Ile149Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I149M) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000367519.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EPM2A | NM_005670.4 | c.446T>C | p.Ile149Thr | missense_variant | 2/4 | ENST00000367519.9 | NP_005661.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EPM2A | ENST00000367519.9 | c.446T>C | p.Ile149Thr | missense_variant | 2/4 | 1 | NM_005670.4 | ENSP00000356489 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251330Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135844
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461650Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727116
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2013 | p.Ile149Thr (ATT>ACT): c.446 T>C in exon 2 of the EPM2A gene (NM_005670.3). The Ile149Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a non-polar Isoleucine residue with a polar Threonine residue. It alters at a position that is not highly conserved across species; however, other nearby missense mutations (K140N and N148Y) have been reported in association with Lafora disease. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ile149Thr is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). - |
Progressive myoclonic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 04, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 149 of the EPM2A protein (p.Ile149Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EPM2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 205439). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at