rs141975071
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_005670.4(EPM2A):c.736C>T(p.Pro246Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
EPM2A
NM_005670.4 missense
NM_005670.4 missense
Scores
5
3
2
Clinical Significance
Conservation
PhyloP100: 9.60
Genes affected
EPM2A (HGNC:3413): (EPM2A glucan phosphatase, laforin) This gene encodes a dual-specificity phosphatase and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. Loss-of-function mutations in this gene have been associated with Lafora disease, a rare, adult-onset recessive neurodegenerative disease, which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of insoluble particles called Lafora bodies, which are derived from glycogen. [provided by RefSeq, Jan 2018]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a domain Tyrosine-protein phosphatase (size 167) in uniprot entity EPM2A_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_005670.4
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EPM2A | NM_005670.4 | c.736C>T | p.Pro246Ser | missense_variant | 4/4 | ENST00000367519.9 | NP_005661.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EPM2A | ENST00000367519.9 | c.736C>T | p.Pro246Ser | missense_variant | 4/4 | 1 | NM_005670.4 | ENSP00000356489 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000205 AC: 51AN: 248664Hom.: 0 AF XY: 0.000208 AC XY: 28AN XY: 134710
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GnomAD4 exome AF: 0.000124 AC: 181AN: 1461784Hom.: 0 Cov.: 32 AF XY: 0.000116 AC XY: 84AN XY: 727198
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GnomAD4 genome AF: 0.000164 AC: 25AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74374
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 22, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 02, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533, 17879451) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 27, 2017 | The p.P246S variant (also known as c.736C>T), located in coding exon 4 of the EPM2A gene, results from a C to T substitution at nucleotide position 736. The proline at codon 246 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Progressive myoclonic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 04, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 246 of the EPM2A protein (p.Pro246Ser). This variant is present in population databases (rs141975071, gnomAD 0.04%). 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: 377059). 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. 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
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Name
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BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
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DANN
Pathogenic
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Pathogenic
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Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
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T;T
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Uncertain
D
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Uncertain
D;D
MutationTaster
Benign
D
ClinPred
D
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at