6-145735363-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_005670.4(EPM2A):c.136G>A(p.Ala46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000673 in 788,066 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 1 hom. )

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5B: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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018208861).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000447 (29/648384) while in subpopulation AMR AF = 0.00226 (9/3988). AF 95% confidence interval is 0.00118. There are 1 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.136G>A	p.Ala46Thr	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>A	p.Ala46Thr	missense_variant	Exon 1 of 4	1	NM_005670.4	ENSP00000356489.3		O95278-1

Frequencies

GnomAD3 genomes

AF:

0.000186

AC:

AN:

139548

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000479

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000422

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000507

GnomAD2 exomes

AF:

0.000439

AC:

AN:

11398

AF XY:

0.000411

show subpopulations

Gnomad AFR exome

AF:

0.00481

Gnomad AMR exome

AF:

0.00245

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000447

AC:

AN:

648384

Hom.:

Cov.:

AF XY:

0.0000533

AC XY:

AN XY:

318758

show subpopulations

African (AFR)

AF:

0.000902

AC:

AN:

12192

American (AMR)

AF:

0.00226

AC:

AN:

3988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6166

East Asian (EAS)

AF:

0.00

AC:

AN:

8634

South Asian (SAS)

AF:

0.0000369

AC:

AN:

27088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1454

European-Non Finnish (NFE)

AF:

0.00000718

AC:

AN:

556928

Other (OTH)

AF:

0.000170

AC:

AN:

23478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000172

AC:

AN:

139682

Hom.:

Cov.:

AF XY:

0.000192

AC XY:

AN XY:

67748

show subpopulations

African (AFR)

AF:

0.000428

AC:

AN:

39716

American (AMR)

AF:

0.000421

AC:

AN:

14246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3256

East Asian (EAS)

AF:

0.00

AC:

AN:

4050

South Asian (SAS)

AF:

0.00

AC:

AN:

3834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63434

Other (OTH)

AF:

0.000502

AC:

AN:

1992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000291

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lafora disease

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jul 31, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A46T variant (also known as c.136G>A), located in coding exon 1 of the EPM2A gene, results from a G to A substitution at nucleotide position 136. The alanine at codon 46 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

May 19, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function -

Progressive myoclonic epilepsy

Uncertain:1

Sep 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 46 of the EPM2A protein (p.Ala46Thr). This variant is present in population databases (no rsID available, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with EPM2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 205444). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Myoclonic epilepsy of Lafora 1

Uncertain:1

Feb 06, 2020

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EPM2A-related disorder

Benign:1

Mar 18, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.33

T;.;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.62

T;T;.;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.28

N;N;N;N

PhyloP100

-0.075

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.31

N;.;.;.

REVEL

Benign

0.16

Sift

Benign

0.59

T;.;.;.

Sift4G

Benign

0.40

T;T;.;.

Polyphen

0.81

P;B;B;.

Vest4

0.046

MutPred

0.48

Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);

MVP

0.88

MPC

0.23

ClinPred

0.011

GERP RS

2.4

PromoterAI

-0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.23

Mutation Taster

=98/2

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