rs374338349

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 14/20 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

Publications

11 publications found

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:

ENSG00000288551 (HGNC:):

ENSG00000288551 links:

EPM2A-DT (HGNC:48990): (EPM2A divergent transcript)

EPM2A-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.136G>C	p.Ala46Pro	missense_variant	Exon 1 of 4	ENST00000367519.9	NP_005661.1	O95278-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9 link	c.136G>C	p.Ala46Pro	missense_variant	Exon 1 of 4	1	NM_005670.4	ENSP00000356489.3		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

GnomAD2 exomes

AF:

0.0103

AC:

117

AN:

11398

AF XY:

0.0108

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 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

African (AFR)

AF:

0.000246

AC:

AN:

12192

American (AMR)

AF:

0.00

AC:

AN:

3988

Ashkenazi Jewish (ASJ)

AF:

0.00568

AC:

AN:

6166

East Asian (EAS)

AF:

0.156

AC:

1349

AN:

8634

South Asian (SAS)

AF:

0.00838

AC:

227

AN:

27090

European-Finnish (FIN)

AF:

0.0432

AC:

365

AN:

8456

Middle Eastern (MID)

AF:

0.00138

AC:

AN:

1454

European-Non Finnish (NFE)

AF:

0.000393

AC:

219

AN:

556928

Other (OTH)

AF:

0.00941

AC:

221

AN:

23476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.633

Heterozygous variant carriers

193

289

386

482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00436

AC:

609

AN:

139682

Hom.:

Cov.:

AF XY:

0.00523

AC XY:

354

AN XY:

67748

show subpopulations

African (AFR)

AF:

0.000504

AC:

AN:

39716

American (AMR)

AF:

0.000632

AC:

AN:

14246

Ashkenazi Jewish (ASJ)

AF:

0.00215

AC:

AN:

3256

East Asian (EAS)

AF:

0.0881

AC:

357

AN:

4050

South Asian (SAS)

AF:

0.00965

AC:

AN:

3834

European-Finnish (FIN)

AF:

0.0168

AC:

135

AN:

8014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000473

AC:

AN:

63434

Other (OTH)

AF:

0.00703

AC:

AN:

1992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Mar 16, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 08, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lafora disease

Benign:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 10, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 21, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive myoclonic epilepsy

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

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

PhyloP100

-0.075

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

PromoterAI

-0.064

Neutral

(source)

gMVP

0.29

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over