rs61758155

Positions:

• chr6-145686205-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005670.4(EPM2A):​c.393G>A​(p.Glu131=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.50

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]

ACMG classification

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	UniProt
EPM2A	NM_005670.4	c.393G>A	p.Glu131=	synonymous_variant	2/4	ENST00000367519.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.393G>A	p.Glu131=	synonymous_variant	2/4	1	NM_005670.4	P1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152120 Hom.: 0 Cov.: 32

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.: 8 AF XY: 0.00309 AC XY: 420 AN XY: 135880

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.: 16 Cov.: 32 AF XY: 0.00300 AC XY: 2181 AN XY: 727098

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.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74424

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.: 1

Bravo AF: 0.00162

EpiCase AF: 0.00207

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 12, 2018	- -
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 -

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

Invitae

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

Other links and lift over

dbSNP: rs61758155; hg19: chr6-146007341;