rs147399860

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_005670.4(EPM2A):c.680C>T(p.Ala227Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,150 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A227A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 5 hom. )

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.993

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a domain Tyrosine-protein phosphatase (size 167) in uniprot entity EPM2A_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_005670.4

BP4

Computational evidence support a benign effect (MetaRNN=0.019255877).

BP6

Variant 6-145635283-G-A is Benign according to our data. Variant chr6-145635283-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196413.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00086 (131/152300) while in subpopulation NFE AF= 0.00125 (85/68032). AF 95% confidence interval is 0.00103. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4 linkuse as main transcript	c.680C>T	p.Ala227Val	missense_variant	3/4	ENST00000367519.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9 linkuse as main transcript	c.680C>T	p.Ala227Val	missense_variant	3/4	1	NM_005670.4	P1	O95278-1

Frequencies

GnomAD3 genomes

AF:

0.000861

AC:

131

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00117

AC:

294

AN:

251418

Hom.:

AF XY:

0.00109

AC XY:

148

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00181

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00123

AC:

1798

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

872

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.00136

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.000860

AC:

131

AN:

152300

Hom.:

Cov.:

AF XY:

0.000765

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00125

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.00105

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00122

AC:

148

EpiCase

AF:

0.00245

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 21, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The EPM2A p.Ala227Val variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs147399860) and ClinVar (classified as uncertain significance by EGL Genetics, Ambry Genetics and Invitae, and as likely benign by GeneDx and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics). The variant was identified in control databases in 317 of 282824 chromosomes (2 homozygous) at a frequency of 0.001121 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 13 of 7222 chromosomes (freq: 0.0018), European (non-Finnish) in 224 of 129136 chromosomes (freq: 0.001735), Latino in 52 of 35438 chromosomes (freq: 0.001467), Ashkenazi Jewish in 9 of 10368 chromosomes (freq: 0.000868), South Asian in 11 of 30616 chromosomes (freq: 0.000359), African in 4 of 24966 chromosomes (freq: 0.00016) and European (Finnish) in 4 of 25124 chromosomes (freq: 0.000159), but was not observed in the East Asian population. The p.Ala227 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2019

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. -

EPM2A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Progressive myoclonic epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Benign

0.70

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.74

T;T;.;T;.;.;.;.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.019

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.30

Polyphen

0.0010

.;B;.;B;.;B;.;.;.

Vest4

0.21, 0.20, 0.23

MVP

0.50

MPC

0.24

ClinPred

0.0066

GERP RS

-7.0

gMVP

0.27

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

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