6-145735475-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_005670.4(EPM2A):c.24G>A(p.Val8Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,212,804 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

EPM2A
NM_005670.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.369

Publications

1 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 6-145735475-C-T is Benign according to our data. Variant chr6-145735475-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137222.

BP7

Synonymous conserved (PhyloP=0.369 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000772 (117/151584) while in subpopulation NFE AF = 0.0014 (95/67762). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.24G>A	p.Val8Val	synonymous_variant	Exon 1 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.24G>A	p.Val8Val	synonymous_variant	Exon 1 of 4	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes

AF:

0.000772

AC:

117

AN:

151476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

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:

0.00140

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000551

AC:

AN:

5446

AF XY:

0.000614

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00159

AC:

1691

AN:

1061220

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

787

AN XY:

506852

show subpopulations

African (AFR)

AF:

0.000280

AC:

AN:

21406

American (AMR)

AF:

0.000478

AC:

AN:

8364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12746

East Asian (EAS)

AF:

0.0000446

AC:

AN:

22432

South Asian (SAS)

AF:

0.00

AC:

AN:

24194

European-Finnish (FIN)

AF:

0.000200

AC:

AN:

19962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2744

European-Non Finnish (NFE)

AF:

0.00174

AC:

1582

AN:

908284

Other (OTH)

AF:

0.00229

AC:

AN:

41088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

103

205

308

410

513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.000772

AC:

117

AN:

151584

Hom.:

Cov.:

AF XY:

0.000635

AC XY:

AN XY:

74074

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41470

American (AMR)

AF:

0.000328

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

67762

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00122

Hom.:

Bravo

AF:

0.000839

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

May 04, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 26, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EPM2A: BP4, BP7

not specified

Benign:2

Oct 28, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 12, 2013

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.

Lafora disease

Benign:1

Jul 22, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.1% (95/67772) (https://gnomad.broadinstitute.org/variant/6-145735475-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with multiple classifications of Likely Benign or Benign (Variation ID:137222). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.

Inborn genetic diseases

Benign:1

Jul 24, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

0.96

PhyloP100

0.37

PromoterAI

-0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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