Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_005670.4(EPM2A):āc.376A>Gā(p.Ile126Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,613,832 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.007952094).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-145686222-T-C is Benign according to our data. Variant chr6-145686222-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167038.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, Benign=4}.
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000515 (752/1461524) while in subpopulation MID AF= 0.00277 (16/5768). AF 95% confidence interval is 0.00174. There are 8 homozygotes in gnomad4_exome. There are 418 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Jun 01, 2023
EPM2A: BP4 -
Benign, criteria provided, single submitter
clinical testing
GeneDx
Apr 09, 2019
- -
Cataract;C1837397:Severe global developmental delay;C4551563:Microcephaly Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Jan 01, 2017
- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 21, 2017
The p.I126V variant (also known as c.376A>G), located in coding exon 2 of the EPM2A gene, results from an A to G substitution at nucleotide position 376. The isoleucine at codon 126 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Benign:1
Benign, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Mar 14, 2014
- -
EPM2A-related disorder Benign:1
Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Mar 23, 2020
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -