Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_005670.4(EPM2A):c.171G>A(p.Pro57Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000173 in 1,156,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P57P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

EPM2A
NM_005670.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.497

Publications

1 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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 6-145735328-C-T is Benign according to our data. Variant chr6-145735328-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1110339.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.497 with no splicing effect.

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
EPM2A	NM_005670.4	MANE Select	c.171G>A	p.Pro57Pro	synonymous	Exon 1 of 4	NP_005661.1
EPM2A	NM_001018041.2		c.171G>A	p.Pro57Pro	synonymous	Exon 1 of 5	NP_001018051.1
EPM2A	NM_001368130.1		c.171G>A	p.Pro57Pro	synonymous	Exon 1 of 3	NP_001355059.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.171G>A	p.Pro57Pro	synonymous	Exon 1 of 4	ENSP00000356489.3
EPM2A	ENST00000435470.2	TSL:1	c.171G>A	p.Pro57Pro	synonymous	Exon 1 of 5	ENSP00000405913.2
EPM2A	ENST00000638262.1	TSL:1	c.171G>A	p.Pro57Pro	synonymous	Exon 1 of 3	ENSP00000492876.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

82722

AF XY:

0.0000212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000173

AC:

AN:

1156230

Hom.:

Cov.:

AF XY:

0.00000352

AC XY:

AN XY:

568576

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22122

American (AMR)

AF:

0.00

AC:

AN:

22716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16710

East Asian (EAS)

AF:

0.0000638

AC:

AN:

15678

South Asian (SAS)

AF:

0.0000143

AC:

AN:

69882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3506

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

938586

Other (OTH)

AF:

0.00

AC:

AN:

43422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.1

(source)

DANN

Benign

0.92

PhyloP100

-0.50

PromoterAI

0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over