dbSNP rs550455609: EPM2A:p.Glu70* (chr6-145735291-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_005670.4(EPM2A):c.208G>T(p.Glu70*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E70E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

EPM2A
NM_005670.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

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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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

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.208G>T	p.Glu70*	stop_gained	Exon 1 of 4	NP_005661.1
EPM2A	NM_001018041.2		c.208G>T	p.Glu70*	stop_gained	Exon 1 of 5	NP_001018051.1
EPM2A	NM_001368130.1		c.208G>T	p.Glu70*	stop_gained	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.208G>T	p.Glu70*	stop_gained	Exon 1 of 4	ENSP00000356489.3
EPM2A	ENST00000435470.2	TSL:1	c.208G>T	p.Glu70*	stop_gained	Exon 1 of 5	ENSP00000405913.2
EPM2A	ENST00000638262.1	TSL:1	c.208G>T	p.Glu70*	stop_gained	Exon 1 of 3	ENSP00000492876.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.50e-7

AC:

AN:

1333770

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

658400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26982

American (AMR)

AF:

0.00

AC:

AN:

30474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22886

East Asian (EAS)

AF:

0.00

AC:

AN:

29188

South Asian (SAS)

AF:

0.0000133

AC:

AN:

74920

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5118

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1048382

Other (OTH)

AF:

0.00

AC:

AN:

54456

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.012

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.82

PhyloP100

1.1

Vest4

0.58

GERP RS

2.6

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=4/196

disease causing (fs/PTC)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over