NM_005670.4:c.143G>C

Variant names:

• chr6-145735356-C-G
• rs946076987
• NM_005670.4:c.143G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005670.4(EPM2A):​c.143G>C​(p.Gly48Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000862 in 1,159,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G48D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.584
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23318627).

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.143G>C	p.Gly48Ala	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.143G>C	p.Gly48Ala	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.143G>C	p.Gly48Ala	missense	Exon 1 of 3	NP_001355059.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.143G>C	p.Gly48Ala	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.143G>C	p.Gly48Ala	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.143G>C	p.Gly48Ala	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.62e-7 AC: 1 AN: 1159926 Hom.: 0 Cov.: 35 AF XY: 0.00000176 AC XY: 1 AN XY: 567000

African (AFR) AF: 0.00 AC: 0 AN: 22946

American (AMR) AF: 0.00 AC: 0 AN: 14584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15970

East Asian (EAS) AF: 0.00 AC: 0 AN: 23072

South Asian (SAS) AF: 0.00 AC: 0 AN: 47050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3148

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 961406

Other (OTH) AF: 0.00 AC: 0 AN: 45354

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.24	N
PhyloP100		0.58
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.29
Sift	Benign	0.12	T
Sift4G	Benign	0.49	T
Polyphen		0.11	B
Vest4		0.12
MutPred		0.50		Loss of catalytic residue at G48 (P = 0.0161)
MVP		0.93
MPC		0.26
ClinPred		0.096	T
GERP RS		2.5
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
gMVP		0.37
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs946076987; hg19: chr6-146056492;