6-145627577-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_005670.4(EPM2A):c.835G>A(p.Gly279Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,878 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G279C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 167) in uniprot entity EPM2A_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_005670.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-145627577-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 834981.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 6-145627577-C-T is Pathogenic according to our data. Variant chr6-145627577-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3099.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4	c.835G>A	p.Gly279Ser	missense_variant	4/4	ENST00000367519.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.835G>A	p.Gly279Ser	missense_variant	4/4	1	NM_005670.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249864 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135196

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000496 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Lafora disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 24, 2017

- -

Progressive myoclonic epilepsy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

This missense change has been observed in individual(s) with Lafora disease (PMID: 9771710, 33773408). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly279 amino acid residue in EPM2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25246353). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects EPM2A function (PMID: 12019207, 14532330). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EPM2A protein function. ClinVar contains an entry for this variant (Variation ID: 3099). This variant is present in population databases (rs137852917, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 279 of the EPM2A protein (p.Gly279Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.;D;.;.;.;.;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.2	M;.;M;.;M;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	D;.;.;.;.;.;.;.
REVEL	Uncertain	0.52
Sift	Benign	0.12	T;.;.;.;.;.;.;.
Sift4G	Uncertain	0.051	T;.;T;T;.;.;.;.
Polyphen		1.0	D;.;D;.;D;.;.;.
Vest4		0.80
MutPred		0.91		Gain of MoRF binding (P = 0.0974);.;Gain of MoRF binding (P = 0.0974);.;Gain of MoRF binding (P = 0.0974);.;.;.;
MVP		0.91
MPC		0.87
ClinPred		0.92	D
GERP RS		5.7
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs137852917; hg19: chr6-145948713; COSMIC: COSV100837401;