rs946076987

chr6-145735356-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_005670.4(EPM2A):c.143G>A(p.Gly48Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,309,652 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.584

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]

EPM2A-DT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain CBM20 (size 123) in uniprot entity EPM2A_HUMAN there are 16 pathogenic changes around while only 4 benign (80%) in NM_005670.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41180414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4	c.143G>A	p.Gly48Asp	missense_variant	1/4	ENST00000367519.9
EPM2A-DT	NR_038246.1	n.52+436C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.143G>A	p.Gly48Asp	missense_variant	1/4	1	NM_005670.4	P1

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 32 AN: 149732 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000268

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000110 AC: 4 AN: 36458 Hom.: 0 AF XY: 0.0000900 AC XY: 2 AN XY: 22214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000418 AC: 485 AN: 1159920 Hom.: 1 Cov.: 35 AF XY: 0.000423 AC XY: 240 AN XY: 566996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000274

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000265

Gnomad4 NFE exome AF: 0.000477

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000214 AC: 32 AN: 149732 Hom.: 0 Cov.: 33 AF XY: 0.000205 AC XY: 15 AN XY: 73034

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.000664

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000268

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000298

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 18, 2018	- -

Lafora disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

EPM2A NM_005670.3 exon 1 p.Gly48Asp (c.143G>A):This variant has not been reported in the literature but is present in 8/29388 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID:377829). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.143G>A (p.G48D) alteration is located in exon 1 (coding exon 1) of the EPM2A gene. This alteration results from a G to A substitution at nucleotide position 143, causing the glycine (G) at amino acid position 48 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Progressive myoclonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 48 of the EPM2A protein (p.Gly48Asp). This variant is present in population databases (no rsID available, 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: 377829). 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: "Benign"; 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Uncertain	0.44	T;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.62	T;T;.;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.55	N;N;N;N
MutationTaster	Benign	0.58	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.0	N;.;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.023	D;.;.;.
Sift4G	Benign	0.11	T;T;.;.
Polyphen		0.11	B;P;P;.
Vest4		0.18
MutPred		0.56		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.95
MPC		0.34
ClinPred		0.078	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs946076987; hg19: chr6-146056492; COSMIC: COSV105281611; COSMIC: COSV105281611;