rs141919651

chr6-145635475-T-Cchr6-145635475-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_005670.4(EPM2A):c.488A>G(p.Asn163Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N163D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.83

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 Uncertain_significance. Variant got 4 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 chr6-145635476-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 373201.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22942191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4	c.488A>G	p.Asn163Ser	missense_variant	3/4	ENST00000367519.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.488A>G	p.Asn163Ser	missense_variant	3/4	1	NM_005670.4	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000167 AC: 42 AN: 251430 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135892

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: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1461720 Hom.: 0 Cov.: 30 AF XY: 0.000186 AC XY: 135 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74352

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2017	A variant of uncertain significance has been identified in the EPM2A gene. The N163S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N163S variant is observed in 41/126670 (0.03%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The N163S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, a different missense change at this residue (N163D) has been reported as pathogenic at GeneDx in association with epilepsy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The EPM2A p.Asn163Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs141919651) and in ClinVar (classified as a VUS by GeneDx in 2017, Invitae in 2018, and Fulgent in 2018). The variant was identified in control databases in 46 of 282834 chromosomes at a frequency of 0.000163 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 43 of 129146 chromosomes (freq: 0.000333), European (Finnish) in 2 of 25122 chromosomes (freq: 0.00008) and South Asian in 1 of 30616 chromosomes (freq: 0.000033); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and Other populations. Another missense change at this residue (N163D) has been reported as likely pathogenic by GeneDx in association with epilepsy. The variant is located with the Dual specificity phosphatase, subgroup, catalytic domain functional domain(s) of the laforin protein, increasing the likelihood that it may have clinical significance. The p.Asn163 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan) do not predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Lafora disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Progressive myoclonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 163 of the EPM2A protein (p.Asn163Ser). This variant is present in population databases (rs141919651, gnomAD 0.03%). 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: 205426). 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. 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	-0.23	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;.;D;.;.;.;.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N;D;.;.;.;.;.;.;.
Sift	Benign	0.33	T;D;.;.;.;.;.;.;.
Polyphen		0.96, 0.98	.;D;.;D;.;D;.;.;.
Vest4		0.60, 0.62, 0.51
MVP		0.81
MPC		0.26
ClinPred		0.29	T
GERP RS		4.8
gMVP		0.60

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: rs141919651; hg19: chr6-145956611;