NM_005670.4:c.163C>A

Variant names:

• chr6-145735336-G-T
• rs187930476
• NM_005670.4:c.163C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q55P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (9 hom., cov: 32)
  • Exomes 𝑓: 0.019 (287 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 4.35
• Publications: 11 publications found

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]

ENSG00000288551 (HGNC:):

EPM2A-DT (HGNC:48990): (EPM2A divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005670.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	NM_005670.4	MANE Select	c.163C>A	p.Gln55Lys	missense	Exon 1 of 4	NP_005661.1
	EPM2A	NM_001018041.2		c.163C>A	p.Gln55Lys	missense	Exon 1 of 5	NP_001018051.1
	EPM2A	NM_001368130.1		c.163C>A	p.Gln55Lys	missense	Exon 1 of 3	NP_001355059.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.163C>A	p.Gln55Lys	missense	Exon 1 of 4	ENSP00000356489.3
	EPM2A	ENST00000435470.2	TSL:1	c.163C>A	p.Gln55Lys	missense	Exon 1 of 5	ENSP00000405913.2
	EPM2A	ENST00000638262.1	TSL:1	c.163C>A	p.Gln55Lys	missense	Exon 1 of 3	ENSP00000492876.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1764 AN: 150154 Hom.: 9 Cov.: 32

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

GnomAD2 exomes AF: 0.0123 AC: 957 AN: 77612 AF XY: 0.0124

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 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.: 30 AF XY: 0.0191 AC XY: 11586 AN XY: 607676

African (AFR) AF: 0.00261 AC: 63 AN: 24162

American (AMR) AF: 0.00667 AC: 156 AN: 23396

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 37 AN: 19586

East Asian (EAS) AF: 0.000220 AC: 5 AN: 22680

South Asian (SAS) AF: 0.00729 AC: 491 AN: 67368

European-Finnish (FIN) AF: 0.0219 AC: 657 AN: 29992

Middle Eastern (MID) AF: 0.00481 AC: 18 AN: 3746

European-Non Finnish (NFE) AF: 0.0220 AC: 21807 AN: 993364

Other (OTH) AF: 0.0145 AC: 707 AN: 48618

GnomAD4 genome AF: 0.0117 AC: 1763 AN: 150262 Hom.: 9 Cov.: 32 AF XY: 0.0111 AC XY: 812 AN XY: 73394

African (AFR) AF: 0.00380 AC: 157 AN: 41328

American (AMR) AF: 0.00747 AC: 113 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3440

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5082

South Asian (SAS) AF: 0.00521 AC: 25 AN: 4802

European-Finnish (FIN) AF: 0.0173 AC: 171 AN: 9870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0186 AC: 1253 AN: 67332

Other (OTH) AF: 0.00766 AC: 16 AN: 2088

Alfa AF: 0.00364 Hom.: 3

Bravo AF: 0.0112

ExAC AF: 0.00768 AC: 326

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jun 19, 2012

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.

Sep 16, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 09, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Aug 09, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EPM2A: PP3, BS1, BS2

Inborn genetic diseases Benign:1

Feb 21, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lafora disease Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.7	L
PhyloP100		4.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.28
Sift	Benign	0.14	T
Sift4G	Benign	0.62	T
Polyphen		0.019	B
Vest4		0.12
MPC		0.31
ClinPred		0.042	T
GERP RS		3.5
PromoterAI		0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.37
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs187930476; hg19: chr6-146056472; COSMIC: COSV107474609; COSMIC: COSV107474609;