rs946076987

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-145735356-C-T
• chr6-145735356-C-G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_005670.4(EPM2A):​c.143G>A​(p.Gly48Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,309,652 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41180414).

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>A	p.Gly48Asp	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.143G>A	p.Gly48Asp	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.143G>A	p.Gly48Asp	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>A	p.Gly48Asp	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.143G>A	p.Gly48Asp	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.143G>A	p.Gly48Asp	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.000214 AC: 32 AN: 149732 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000664

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: 0.000268

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000110 AC: 4 AN: 36458 AF XY: 0.0000900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000418 AC: 485 AN: 1159920 Hom.: 1 Cov.: 35 AF XY: 0.000423 AC XY: 240 AN XY: 566996

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

American (AMR) AF: 0.000274 AC: 4 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: 0.000265 AC: 7 AN: 26396

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

European-Non Finnish (NFE) AF: 0.000477 AC: 459 AN: 961400

Other (OTH) AF: 0.000331 AC: 15 AN: 45354

GnomAD4 genome AF: 0.000214 AC: 32 AN: 149732 Hom.: 0 Cov.: 33 AF XY: 0.000205 AC XY: 15 AN XY: 73034

African (AFR) AF: 0.0000971 AC: 4 AN: 41194

American (AMR) AF: 0.000664 AC: 10 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9708

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

European-Non Finnish (NFE) AF: 0.000268 AC: 18 AN: 67134

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

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000298

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Lafora disease (1)
-	1	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.58
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.023	D
Sift4G	Benign	0.11	T
Polyphen		0.11	B
Vest4		0.18
MutPred		0.56		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.95
MPC		0.34
ClinPred		0.078	T
GERP RS		2.5
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
gMVP		0.44
Mutation Taster		=88/12	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; COSMIC: COSV105281611; COSMIC: COSV105281611;