6-145686196-C-T

Position:

chr6-145686196-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_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 benign 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

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 -19 ACMG points.

BP4

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

BP6

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

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/exons	MANE	Protein	UniProt
EPM2A	NM_005670.4 linkuse as main transcript	c.402G>A	p.Gly134Gly	synonymous_variant	2/4	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.402G>A	p.Gly134Gly	synonymous_variant	2/4	1	NM_005670.4	ENSP00000356489.3		O95278-1

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

GnomAD3 exomes

AF:

0.214

AC:

53770

AN:

251320

Hom.:

7079

AF XY:

0.210

AC XY:

28476

AN XY:

135826

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 SAS exome

AF:

0.159

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

Gnomad4 AFR exome

AF:

0.0356

Gnomad4 AMR exome

AF:

0.352

Gnomad4 ASJ exome

AF:

0.253

Gnomad4 EAS exome

AF:

0.00509

Gnomad4 SAS exome

AF:

0.163

Gnomad4 FIN exome

AF:

0.225

Gnomad4 NFE exome

AF:

0.246

Gnomad4 OTH exome

AF:

0.207

GnomAD4 genome

AF:

0.183

AC:

27795

AN:

152078

Hom.:

3303

Cov.:

AF XY:

0.180

AC XY:

13395

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0449

Gnomad4 AMR

AF:

0.284

Gnomad4 ASJ

AF:

0.254

Gnomad4 EAS

AF:

0.00810

Gnomad4 SAS

AF:

0.164

Gnomad4 FIN

AF:

0.226

Gnomad4 NFE

AF:

0.245

Gnomad4 OTH

AF:

0.179

Alfa

AF:

0.201

Hom.:

1884

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

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -

Lafora disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 29, 2017

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.72

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

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