EPM2A p.Val81Met

Variant names:

• chr6-145735258-C-T
• rs747386643
• NM_005670.4:c.241G>A
• EPM2A p.Val81Met

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005670.4(EPM2A):​c.241G>A​(p.Val81Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,526,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V81V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0900
• Publications: 0 publications found

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]

ENSG00000288551 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_005670.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13638186).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	NM_005670.4	MANE Select	c.241G>A	p.Val81Met	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360071.2		c.-429G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001347000.1	O95278-8
	EPM2A	NM_001368131.1		c.-127G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001355060.1	O95278-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.241G>A	p.Val81Met	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.241G>A	p.Val81Met	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.241G>A	p.Val81Met	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151556 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.0000590

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000345 AC: 5 AN: 144842 AF XY: 0.0000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000345

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000618 AC: 85 AN: 1375038 Hom.: 0 Cov.: 30 AF XY: 0.0000500 AC XY: 34 AN XY: 680072

African (AFR) AF: 0.0000345 AC: 1 AN: 29026

American (AMR) AF: 0.000114 AC: 4 AN: 34998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23732

East Asian (EAS) AF: 0.00 AC: 0 AN: 33236

South Asian (SAS) AF: 0.00 AC: 0 AN: 77432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 0.0000730 AC: 78 AN: 1068060

Other (OTH) AF: 0.0000356 AC: 2 AN: 56154

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151556 Hom.: 0 Cov.: 32 AF XY: 0.0000675 AC XY: 5 AN XY: 74028

African (AFR) AF: 0.0000242 AC: 1 AN: 41398

American (AMR) AF: 0.0000657 AC: 1 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67816

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000144 Hom.: 1

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.090
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.26
Sift	Benign	0.062	T
Sift4G	Benign	0.10	T
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.31
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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.

Other links and lift over

dbSNP: rs747386643;

hg19: chr6-146056394;