6-145735351-C-T

Variant names:

• chr6-145735351-C-T
• rs753397854
• NM_005670.4:c.148G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005670.4(EPM2A):​c.148G>A​(p.Gly50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,204,134 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G50W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 0.706
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18953064).

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.148G>A	p.Gly50Arg	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.148G>A	p.Gly50Arg	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.148G>A	p.Gly50Arg	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.148G>A	p.Gly50Arg	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.148G>A	p.Gly50Arg	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.148G>A	p.Gly50Arg	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.000321 AC: 47 AN: 146190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000679

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000460

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000524 AC: 22 AN: 41974 AF XY: 0.000510

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: 0.00108

Gnomad NFE exome AF: 0.000925

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000628 AC: 664 AN: 1057816 Hom.: 0 Cov.: 34 AF XY: 0.000606 AC XY: 313 AN XY: 516144

African (AFR) AF: 0.0000496 AC: 1 AN: 20162

American (AMR) AF: 0.00 AC: 0 AN: 12196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12534

East Asian (EAS) AF: 0.00 AC: 0 AN: 14704

South Asian (SAS) AF: 0.000335 AC: 16 AN: 47730

European-Finnish (FIN) AF: 0.00117 AC: 19 AN: 16214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2586

European-Non Finnish (NFE) AF: 0.000689 AC: 615 AN: 893200

Other (OTH) AF: 0.000338 AC: 13 AN: 38490

GnomAD4 genome AF: 0.000321 AC: 47 AN: 146318 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 24 AN XY: 71326

African (AFR) AF: 0.0000245 AC: 1 AN: 40762

American (AMR) AF: 0.0000678 AC: 1 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.00 AC: 0 AN: 4706

South Asian (SAS) AF: 0.000459 AC: 2 AN: 4362

European-Finnish (FIN) AF: 0.00121 AC: 11 AN: 9086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000485 AC: 32 AN: 66020

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000253

ExAC AF: 0.000215 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	1	-	Inborn genetic diseases (1)
-	1	-	Lafora disease (1)
-	1	-	Myoclonic epilepsy of Lafora 1 (1)
-	1	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.075	D
MutationAssessor	Benign	0.90	L
PhyloP100		0.71
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.28
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.032	D
Polyphen		0.012	B
Vest4		0.15
MutPred		0.34		Gain of methylation at G50 (P = 0.0175)
MVP		0.92
MPC		0.33
ClinPred		0.061	T
GERP RS		2.5
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
gMVP		0.44
Mutation Taster		=91/9	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: rs753397854; hg19: chr6-146056487;