dbSNP rs946076987: EPM2A:p.Gly48Ala (chr6-145735356-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005670.4(EPM2A):c.143G>C(p.Gly48Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000862 in 1,159,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G48D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.584

Publications

0 publications found

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:

ENSG00000288551 (HGNC:):

ENSG00000288551 links:

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

EPM2A-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23318627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.143G>C	p.Gly48Ala	missense_variant	Exon 1 of 4	ENST00000367519.9	NP_005661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9 link	c.143G>C	p.Gly48Ala	missense_variant	Exon 1 of 4	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.62e-7

AC:

AN:

1159926

Hom.:

Cov.:

AF XY:

0.00000176

AC XY:

AN XY:

567000

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22946

American (AMR)

AF:

0.00

AC:

AN:

14584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15970

East Asian (EAS)

AF:

0.00

AC:

AN:

23072

South Asian (SAS)

AF:

0.00

AC:

AN:

47050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3148

European-Non Finnish (NFE)

AF:

0.00000104

AC:

AN:

961406

Other (OTH)

AF:

0.00

AC:

AN:

45354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Uncertain

0.42

T;.;.;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.68

T;T;.;T

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.24

N;N;N;N

PhyloP100

0.58

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.89

N;.;.;.

REVEL

Benign

0.29

Sift

Benign

0.12

T;.;.;.

Sift4G

Benign

0.49

T;T;.;.

Polyphen

0.11

B;B;B;.

Vest4

0.12

MutPred

0.50

Loss of catalytic residue at G48 (P = 0.0161);Loss of catalytic residue at G48 (P = 0.0161);Loss of catalytic residue at G48 (P = 0.0161);Loss of catalytic residue at G48 (P = 0.0161);

MVP

0.93

MPC

0.26

ClinPred

0.096

GERP RS

2.5

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

gMVP

0.37

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over