6-145686196-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 1P and 17B. PP3BP6_Very_StrongBP7BA1

The NM_005670.4(EPM2A):c.402G>A(p.Gly134Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,612,596 control chromosomes in the GnomAD database, including 44,761 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3303 hom., cov: 32)

Exomes 𝑓: 0.23 ( 41458 hom. )

Consequence

EPM2A
NM_005670.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.706

Publications

12 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 Gene-Disease associations (from GenCC):

Lafora disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia

EPM2A links:

ENSG00000307801 (HGNC:):

ENSG00000307801 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

PP3

REVEL computational evidence supports a deleterious effect, 0.732

BP6

Variant 6-145686196-C-T is Benign according to our data. Variant chr6-145686196-C-T is described in ClinVar as Benign. ClinVar VariationId is 129005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.706 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.402G>A	p.Gly134Gly	synonymous_variant	Exon 2 of 4	ENST00000367519.9	NP_005661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9 link	c.402G>A	p.Gly134Gly	synonymous_variant	Exon 2 of 4	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27793

AN:

151958

Hom.:

3304

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0451

Gnomad AMI

AF:

0.500

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.00789

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.226

Gnomad MID

AF:

0.124

Gnomad NFE

AF:

0.245

Gnomad OTH

AF:

0.182

GnomAD2 exomes

AF:

0.214

AC:

53770

AN:

251320

AF XY:

0.210

show subpopulations

Gnomad AFR exome

AF:

0.0384

Gnomad AMR exome

AF:

0.356

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.00827

Gnomad FIN exome

AF:

0.226

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.208

GnomAD4 exome

AF:

0.230

AC:

335864

AN:

1460518

Hom.:

41458

Cov.:

AF XY:

0.228

AC XY:

165746

AN XY:

726626

show subpopulations

African (AFR)

AF:

0.0356

AC:

1193

AN:

33468

American (AMR)

AF:

0.352

AC:

15736

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6614

AN:

26122

East Asian (EAS)

AF:

0.00509

AC:

202

AN:

39684

South Asian (SAS)

AF:

0.163

AC:

14075

AN:

86240

European-Finnish (FIN)

AF:

0.225

AC:

12010

AN:

53408

Middle Eastern (MID)

AF:

0.124

AC:

715

AN:

5766

European-Non Finnish (NFE)

AF:

0.246

AC:

272805

AN:

1110816

Other (OTH)

AF:

0.207

AC:

12514

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

13025

26050

39076

52101

65126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9106

18212

27318

36424

45530

<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:

0.183

AC:

27795

AN:

152078

Hom.:

3303

Cov.:

AF XY:

0.180

AC XY:

13395

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0449

AC:

1865

AN:

41516

American (AMR)

AF:

0.284

AC:

4330

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

880

AN:

3470

East Asian (EAS)

AF:

0.00810

AC:

AN:

5182

South Asian (SAS)

AF:

0.164

AC:

791

AN:

4822

European-Finnish (FIN)

AF:

0.226

AC:

2387

AN:

10556

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.245

AC:

16630

AN:

67954

Other (OTH)

AF:

0.179

AC:

379

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1098

2197

3295

4394

5492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.182

Hom.:

2521

Bravo

AF:

0.181

Asia WGS

AF:

0.100

AC:

352

AN:

3478

EpiCase

AF:

0.229

EpiControl

AF:

0.227

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 51. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Lafora disease

Benign:1

Apr 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

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. -

Progressive myoclonic epilepsy

Benign:1

Feb 04, 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

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.71

PromoterAI

0.036

Neutral

(source)

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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