rs374826256

Positions:

• chr6-145735264-C-A
• chr6-145735264-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005670.4(EPM2A):​c.235G>T​(p.Gly79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0390

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPM2A	NM_005670.4	c.235G>T	p.Gly79Cys	missense_variant	1/4	ENST00000367519.9	NP_005661.1
EPM2A-DT	NR_038246.1	n.52+344C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9	c.235G>T	p.Gly79Cys	missense_variant	1/4	1	NM_005670.4	ENSP00000356489	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1366366 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 675480

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 04, 2020

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces glycine with cysteine at codon 79 of the EPM2A protein (p.Gly79Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. This variant has not been reported in the literature in individuals with EPM2A-related conditions. 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.;.
Eigen	Benign	0.041
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.58	T;T;.;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.0	L;L;L;L
MutationTaster	Benign	0.51	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.3	N;.;.;.
REVEL	Uncertain	0.52
Sift	Benign	0.18	T;.;.;.
Sift4G	Benign	0.15	T;T;.;.
Polyphen		0.98	D;D;D;.
Vest4		0.17
MutPred		0.66		Gain of catalytic residue at P78 (P = 0.0157);Gain of catalytic residue at P78 (P = 0.0157);Gain of catalytic residue at P78 (P = 0.0157);Gain of catalytic residue at P78 (P = 0.0157);
MVP		0.97
MPC		0.26
ClinPred		0.74	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.53

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: rs374826256; hg19: chr6-146056400;