NM_005670.4:c.67G>C

Variant names:

• chr6-145735432-C-G
• rs1060503233
• NM_005670.4:c.67G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_005670.4(EPM2A):​c.67G>C​(p.Val23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000452 in 1,106,734 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. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.0000045 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• 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 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=0.3232745).

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.67G>C	p.Val23Leu	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360071.2		c.-603G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001347000.1	O95278-8
	EPM2A	NM_001368131.1		c.-301G>C		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.67G>C	p.Val23Leu	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.67G>C	p.Val23Leu	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.67G>C	p.Val23Leu	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000452 AC: 5 AN: 1106734 Hom.: 0 Cov.: 34 AF XY: 0.00000749 AC XY: 4 AN XY: 533884

African (AFR) AF: 0.0000441 AC: 1 AN: 22652

American (AMR) AF: 0.00 AC: 0 AN: 16888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15836

East Asian (EAS) AF: 0.00 AC: 0 AN: 22564

South Asian (SAS) AF: 0.00 AC: 0 AN: 33808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2974

European-Non Finnish (NFE) AF: 0.00000324 AC: 3 AN: 927134

Other (OTH) AF: 0.0000233 AC: 1 AN: 42962

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.18
Sift	Benign	0.59	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.35		Loss of sheet (P = 0.0084)
MVP		0.95
MPC		0.24
ClinPred		0.17	T
GERP RS		3.5
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.34
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs1060503233; hg19: chr6-146056568;