6-145735340-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005670.4(EPM2A):c.159C>G(p.Ala53Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 1,386,774 control chromosomes in the GnomAD database, including 246,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A53A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.63 ( 30260 hom., cov: 31)

Exomes 𝑓: 0.59 ( 216486 hom. )

Consequence

EPM2A
NM_005670.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.643

Publications

15 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 6-145735340-G-C is Benign according to our data. Variant chr6-145735340-G-C is described in ClinVar as Benign. ClinVar VariationId is 95306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.643 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.159C>G	p.Ala53Ala	synonymous_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.159C>G	p.Ala53Ala	synonymous_variant	Exon 1 of 4	1	NM_005670.4	ENSP00000356489.3		O95278-1

Frequencies

GnomAD3 genomes

AF:

0.631

AC:

94339

AN:

149600

Hom.:

30225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.708

Gnomad AMI

AF:

0.634

Gnomad AMR

AF:

0.713

Gnomad ASJ

AF:

0.615

Gnomad EAS

AF:

0.742

Gnomad SAS

AF:

0.485

Gnomad FIN

AF:

0.504

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.586

Gnomad OTH

AF:

0.643

GnomAD2 exomes

AF:

0.614

AC:

46781

AN:

76174

AF XY:

0.591

show subpopulations

Gnomad AFR exome

AF:

0.687

Gnomad AMR exome

AF:

0.804

Gnomad ASJ exome

AF:

0.628

Gnomad EAS exome

AF:

0.764

Gnomad FIN exome

AF:

0.528

Gnomad NFE exome

AF:

0.588

Gnomad OTH exome

AF:

0.622

GnomAD4 exome

AF:

0.589

AC:

728552

AN:

1237064

Hom.:

216486

Cov.:

AF XY:

0.585

AC XY:

355979

AN XY:

608792

show subpopulations

African (AFR)

AF:

0.706

AC:

17623

AN:

24958

American (AMR)

AF:

0.778

AC:

18554

AN:

23860

Ashkenazi Jewish (ASJ)

AF:

0.611

AC:

12265

AN:

20072

East Asian (EAS)

AF:

0.727

AC:

17584

AN:

24180

South Asian (SAS)

AF:

0.476

AC:

30429

AN:

63978

European-Finnish (FIN)

AF:

0.522

AC:

16086

AN:

30802

Middle Eastern (MID)

AF:

0.595

AC:

2191

AN:

3680

European-Non Finnish (NFE)

AF:

0.587

AC:

584416

AN:

996356

Other (OTH)

AF:

0.598

AC:

29404

AN:

49178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

14506

29012

43517

58023

72529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17322

34644

51966

69288

86610

<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:

0.631

AC:

94416

AN:

149710

Hom.:

30260

Cov.:

AF XY:

0.627

AC XY:

45811

AN XY:

73052

show subpopulations

African (AFR)

AF:

0.708

AC:

29212

AN:

41236

American (AMR)

AF:

0.714

AC:

10774

AN:

15094

Ashkenazi Jewish (ASJ)

AF:

0.615

AC:

2108

AN:

3428

East Asian (EAS)

AF:

0.741

AC:

3740

AN:

5044

South Asian (SAS)

AF:

0.486

AC:

2341

AN:

4820

European-Finnish (FIN)

AF:

0.504

AC:

4891

AN:

9710

Middle Eastern (MID)

AF:

0.555

AC:

162

AN:

292

European-Non Finnish (NFE)

AF:

0.586

AC:

39291

AN:

67106

Other (OTH)

AF:

0.638

AC:

1321

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1766

3532

5299

7065

8831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

764

1528

2292

3056

3820

<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:

0.507

Hom.:

1432

Bravo

AF:

0.653

Asia WGS

AF:

0.567

AC:

1844

AN:

3250

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 94% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 87. Only high quality variants are reported. -

Dec 14, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Apr 29, 2017

Athena Diagnostics

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lafora disease

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

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

-0.72

CADD

Benign

8.3

(source)

DANN

Benign

0.63

PhyloP100

-0.64

PromoterAI

-0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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