6-145735342-C-T

Position:

chr6-145735342-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_005670.4(EPM2A):c.157G>A(p.Ala53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000888 in 1,362,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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. A53A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.63

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:

EPM2A (HGNC:):

EPM2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034620583).

BP6

Variant 6-145735342-C-T is Benign according to our data. Variant chr6-145735342-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205430.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000891 (108/1212682) while in subpopulation MID AF= 0.002 (7/3496). AF 95% confidence interval is 0.000939. There are 0 homozygotes in gnomad4_exome. There are 55 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPM2A	NM_005670.4 linkuse as main transcript	c.157G>A	p.Ala53Thr	missense_variant	1/4	ENST00000367519.9	NP_005661.1	O95278-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9 linkuse as main transcript	c.157G>A	p.Ala53Thr	missense_variant	1/4	1	NM_005670.4	ENSP00000356489.3		O95278-1

Frequencies

GnomAD3 genomes

AF:

0.0000866

AC:

AN:

150056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00146

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000104

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000214

AC:

AN:

69968

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

41000

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000163

Gnomad ASJ exome

AF:

0.00114

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000128

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.000507

GnomAD4 exome

AF:

0.0000891

AC:

108

AN:

1212682

Hom.:

Cov.:

AF XY:

0.0000923

AC XY:

AN XY:

595930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000186

Gnomad4 ASJ exome

AF:

0.000827

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000155

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000599

Gnomad4 OTH exome

AF:

0.000271

GnomAD4 genome

AF:

0.0000866

AC:

AN:

150056

Hom.:

Cov.:

AF XY:

0.0000546

AC XY:

AN XY:

73204

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000663

Gnomad4 ASJ

AF:

0.00146

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000104

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000131

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 53 of the EPM2A protein (p.Ala53Thr). This variant is present in population databases (rs763719276, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with EPM2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 205430). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.32

T;.;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.64

T;T;.;T

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.035

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.3

L;L;L;L

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.33

N;.;.;.

REVEL

Benign

0.14

Sift

Benign

0.60

T;.;.;.

Sift4G

Benign

0.15

T;T;.;.

Polyphen

0.014

B;B;B;.

Vest4

0.11

MutPred

0.25

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);

MVP

0.81

MPC

0.24

ClinPred

0.052

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.26

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