Genetic Variant NM_005670.4:c.163C>G (chr6-145735336-G-C) – 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.163C>G(p.Gln55Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000217 in 1,383,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. Q55P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.35

Publications

11 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=0.25504282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4 link	c.163C>G	p.Gln55Glu	missense_variant	Exon 1 of 4	ENST00000367519.9	NP_005661.1	O95278-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9 link	c.163C>G	p.Gln55Glu	missense_variant	Exon 1 of 4	1	NM_005670.4	ENSP00000356489.3		O95278-1

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000162

AC:

AN:

1232942

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

607692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24162

American (AMR)

AF:

0.00

AC:

AN:

23396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19586

East Asian (EAS)

AF:

0.00

AC:

AN:

22680

South Asian (SAS)

AF:

0.00

AC:

AN:

67368

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3746

European-Non Finnish (NFE)

AF:

0.00000201

AC:

AN:

993390

Other (OTH)

AF:

0.00

AC:

AN:

48620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

AF:

0.00000666

AC:

AN:

150160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41210

American (AMR)

AF:

0.00

AC:

AN:

15100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5098

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67342

Other (OTH)

AF:

0.00

AC:

AN:

2066

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.32

T;.;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.63

T;T;.;T

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.1

L;L;L;L

PhyloP100

4.4

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.21

N;.;.;.

REVEL

Benign

0.26

Sift

Benign

0.82

T;.;.;.

Sift4G

Benign

0.18

T;T;.;.

Polyphen

0.0010

B;B;B;.

Vest4

0.13

MutPred

0.38

Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);

MVP

0.95

MPC

0.26

ClinPred

0.17

GERP RS

3.5

PromoterAI

0.069

Neutral

(source)

gMVP

0.30

Mutation Taster

=95/5

polymorphism

(source)

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

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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