rs753397854

Positions:

• chr6-145735351-C-A
• chr6-145735351-C-G
• chr6-145735351-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001360071.2(EPM2A):​c.-522G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,057,814 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: EPM2A NM_001360071.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.706

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3528105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPM2A	NM_005670.4	c.148G>T	p.Gly50Trp	missense_variant	1/4	ENST00000367519.9	NP_005661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9	c.148G>T	p.Gly50Trp	missense_variant	1/4	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000284 AC: 3 AN: 1057814 Hom.: 0 Cov.: 34 AF XY: 0.00000387 AC XY: 2 AN XY: 516144

Gnomad4 AFR exome AF: 0.0000992

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000260

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.148G>T (p.G50W) alteration is located in exon 1 (coding exon 1) of the EPM2A gene. This alteration results from a G to T substitution at nucleotide position 148, causing the glycine (G) at amino acid position 50 to be replaced by a tryptophan (W). 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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2021

This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 50 of the EPM2A protein (p.Gly50Trp). 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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with EPM2A-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.63	T;T;.;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.4	L;L;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N;.;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;.;.;.
Sift4G	Uncertain	0.0030	D;D;.;.
Polyphen		0.97	D;D;D;.
Vest4		0.21
MutPred		0.35		Loss of disorder (P = 0.011);Loss of disorder (P = 0.011);Loss of disorder (P = 0.011);Loss of disorder (P = 0.011);
MVP		0.96
MPC		0.71
ClinPred		0.68	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
gMVP		0.47

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: rs753397854; hg19: chr6-146056487;