rs374338349

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005670.4(EPM2A):c.136G>C(p.Ala46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 788,066 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0044 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 75 hom. )

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.0750

Variant links:

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 links:

EPM2A-DT (HGNC:):

EPM2A-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0021043122).

BP6

Variant 6-145735363-C-G is Benign according to our data. Variant chr6-145735363-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 162617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4 linkuse as main transcript	c.136G>C	p.Ala46Pro	missense_variant	1/4	ENST00000367519.9
EPM2A-DT	NR_038246.1 linkuse as main transcript	n.52+443C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9 linkuse as main transcript	c.136G>C	p.Ala46Pro	missense_variant	1/4	1	NM_005670.4	P1	O95278-1

Frequencies

GnomAD3 genomes

AF:

0.00431

AC:

602

AN:

139548

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000505

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000633

Gnomad ASJ

AF:

0.00215

Gnomad EAS

AF:

0.0878

Gnomad SAS

AF:

0.00919

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000473

Gnomad OTH

AF:

0.00507

GnomAD3 exomes

AF:

0.0103

AC:

117

AN:

11398

Hom.:

AF XY:

0.0108

AC XY:

AN XY:

7306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00704

Gnomad EAS exome

AF:

0.182

Gnomad SAS exome

AF:

0.0150

Gnomad FIN exome

AF:

0.0382

Gnomad NFE exome

AF:

0.000987

Gnomad OTH exome

AF:

0.00773

GnomAD4 exome

AF:

0.00373

AC:

2421

AN:

648384

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

1196

AN XY:

318756

show subpopulations

Gnomad4 AFR exome

AF:

0.000246

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00568

Gnomad4 EAS exome

AF:

0.156

Gnomad4 SAS exome

AF:

0.00838

Gnomad4 FIN exome

AF:

0.0432

Gnomad4 NFE exome

AF:

0.000393

Gnomad4 OTH exome

AF:

0.00941

GnomAD4 genome

AF:

0.00436

AC:

609

AN:

139682

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

354

AN XY:

67748

show subpopulations

Gnomad4 AFR

AF:

0.000504

Gnomad4 AMR

AF:

0.000632

Gnomad4 ASJ

AF:

0.00215

Gnomad4 EAS

AF:

0.0881

Gnomad4 SAS

AF:

0.00965

Gnomad4 FIN

AF:

0.0168

Gnomad4 NFE

AF:

0.000473

Gnomad4 OTH

AF:

0.00703

Alfa

AF:

0.000595

Hom.:

Bravo

AF:

0.00359

ExAC

AF:

0.00683

AC:

Asia WGS

AF:

0.0430

AC:

138

AN:

3234

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Lafora disease

Benign:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 10, 2021	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 21, 2017

- -

Progressive myoclonic epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.63

T;T;.;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.6

L;L;L;L

MutationTaster

Benign

0.56

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.11

N;.;.;.

REVEL

Benign

0.25

Sift

Benign

0.36

T;.;.;.

Sift4G

Benign

0.28

T;T;.;.

Polyphen

0.96

D;P;P;.

Vest4

0.15

MPC

0.31

ClinPred

0.048

GERP RS

2.4

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over