6-145735336-G-T

Position:

chr6-145735336-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005670.4(EPM2A):c.163C>A(p.Gln55Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0186 in 1,383,174 control chromosomes in the GnomAD database, including 296 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 9 hom., cov: 32)

Exomes 𝑓: 0.019 ( 287 hom. )

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 4.35

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:

EPM2A (HGNC:):

EPM2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077129304).

BP6

Variant 6-145735336-G-T is Benign according to our data. Variant chr6-145735336-G-T is described in ClinVar as [Benign]. Clinvar id is 129003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-145735336-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1763/150262) while in subpopulation NFE AF= 0.0186 (1253/67332). AF 95% confidence interval is 0.0178. There are 9 homozygotes in gnomad4. There are 812 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPM2A	NM_005670.4 linkuse as main transcript	c.163C>A	p.Gln55Lys	missense_variant	1/4	ENST00000367519.9	NP_005661.1	O95278-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9 linkuse as main transcript	c.163C>A	p.Gln55Lys	missense_variant	1/4	1	NM_005670.4	ENSP00000356489.3		O95278-1

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1764

AN:

150154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.00748

Gnomad ASJ

AF:

0.00145

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00520

Gnomad FIN

AF:

0.0173

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.00774

GnomAD3 exomes

AF:

0.0123

AC:

957

AN:

77612

Hom.:

AF XY:

0.0124

AC XY:

552

AN XY:

44600

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00731

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0209

Gnomad OTH exome

AF:

0.0109

GnomAD4 exome

AF:

0.0194

AC:

23941

AN:

1232912

Hom.:

287

Cov.:

AF XY:

0.0191

AC XY:

11586

AN XY:

607676

show subpopulations

Gnomad4 AFR exome

AF:

0.00261

Gnomad4 AMR exome

AF:

0.00667

Gnomad4 ASJ exome

AF:

0.00189

Gnomad4 EAS exome

AF:

0.000220

Gnomad4 SAS exome

AF:

0.00729

Gnomad4 FIN exome

AF:

0.0219

Gnomad4 NFE exome

AF:

0.0220

Gnomad4 OTH exome

AF:

0.0145

GnomAD4 genome

AF:

0.0117

AC:

1763

AN:

150262

Hom.:

Cov.:

AF XY:

0.0111

AC XY:

812

AN XY:

73394

show subpopulations

Gnomad4 AFR

AF:

0.00380

Gnomad4 AMR

AF:

0.00747

Gnomad4 ASJ

AF:

0.00145

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00521

Gnomad4 FIN

AF:

0.0173

Gnomad4 NFE

AF:

0.0186

Gnomad4 OTH

AF:

0.00766

Alfa

AF:

0.00364

Hom.:

Bravo

AF:

0.0112

ExAC

AF:

0.00768

AC:

326

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 16, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2012	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. -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	EPM2A: PP3, BS1, BS2 -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2017

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Lafora disease

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.45

T;.;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.66

T;T;.;T

MetaRNN

Benign

0.0077

T;T;T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

1.7

L;L;L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.47

N;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.14

T;.;.;.

Sift4G

Benign

0.62

T;T;.;.

Polyphen

0.019

B;B;B;.

Vest4

0.12

MPC

0.31

ClinPred

0.042

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over