6-145735336-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 12/18 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

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-DT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain CBM20 (size 123) in uniprot entity EPM2A_HUMAN there are 16 pathogenic changes around while only 4 benign (80%) in NM_005670.4
• 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 GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4	c.163C>A	p.Gln55Lys	missense_variant	1/4	ENST00000367519.9
EPM2A-DT	NR_038246.1	n.52+416G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.163C>A	p.Gln55Lys	missense_variant	1/4	1	NM_005670.4	P1

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

GnomAD3 exomes AF: 0.0123 AC: 957 AN: 77612 Hom.: 12 AF XY: 0.0124 AC XY: 552 AN XY: 44600

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

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.: 9 Cov.: 32 AF XY: 0.0111 AC XY: 812 AN XY: 73394

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.: 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:3

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

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 2017	- -
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

Invitae

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	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;T;.;T
MetaRNN	Benign	0.0077	T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.7	L;L;L;L
MutationTaster	Benign	0.87	D
PrimateAI	Pathogenic	0.82	D
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	T
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

Other links and lift over

dbSNP: rs187930476; hg19: chr6-146056472;