EPM2A p.Val23Leu

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_005670.4(EPM2A):c.67G>T(p.Val23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V23V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EPM2A
NM_005670.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.72

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:

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new If you want to explore the variant's impact on the transcript NM_005670.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_005670.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31955385).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005670.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPM2A	NM_005670.4	MANE Select	c.67G>T	p.Val23Leu	missense	Exon 1 of 4	NP_005661.1	O95278-1
EPM2A	NM_001360071.2		c.-603G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001347000.1	O95278-8
EPM2A	NM_001368131.1		c.-301G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001355060.1	O95278-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.67G>T	p.Val23Leu	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
EPM2A	ENST00000435470.2	TSL:1	c.67G>T	p.Val23Leu	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
EPM2A	ENST00000638262.1	TSL:1	c.67G>T	p.Val23Leu	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1106734

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

533884

African (AFR)

AF:

0.00

AC:

AN:

22652

American (AMR)

AF:

0.00

AC:

AN:

16888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15836

East Asian (EAS)

AF:

0.00

AC:

AN:

22564

South Asian (SAS)

AF:

0.00

AC:

AN:

33808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21916

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2974

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

927134

Other (OTH)

AF:

0.00

AC:

AN:

42962

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.32

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.9

PhyloP100

1.7

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.050

REVEL

Benign

0.18

Sift

Benign

0.59

Sift4G

Benign

0.91

PromoterAI

-0.060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.34

Mutation Taster

=85/15

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over