rs61758155

Positions:

chr6-145686205-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005670.4(EPM2A):c.393G>A(p.Glu131Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,613,746 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 16 hom. )

Consequence

EPM2A
NM_005670.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.50

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:

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=-0.35).

BP6

Variant 6-145686205-C-T is Benign according to our data. Variant chr6-145686205-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-145686205-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.5 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00209 (318/152238) while in subpopulation NFE AF= 0.00307 (209/68012). AF 95% confidence interval is 0.00273. There are 0 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.393G>A	p.Glu131Glu	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 link	c.393G>A	p.Glu131Glu	synonymous_variant	2/4	1	NM_005670.4	ENSP00000356489.3		O95278-1

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00746

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00307

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00296

AC:

743

AN:

251410

Hom.:

AF XY:

0.00309

AC XY:

420

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00758

Gnomad NFE exome

AF:

0.00470

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00307

AC:

4483

AN:

1461508

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

2181

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00917

Gnomad4 NFE exome

AF:

0.00340

Gnomad4 OTH exome

AF:

0.00255

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152238

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00746

Gnomad4 NFE

AF:

0.00307

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00247

Hom.:

Bravo

AF:

0.00162

EpiCase

AF:

0.00207

EpiControl

AF:

0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 23, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	EPM2A: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 12, 2018	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 24, 2014	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2016

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.3

DANN

Benign

0.62

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