rs104893950

Variant names:

• chr6-145627691-G-A
• rs104893950
• NM_005670.4:c.721C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-145627691-G-A
• chr6-145627691-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Strong PS3 PP5_Very_Strong

The NM_005670.4(EPM2A):​c.721C>T​(p.Arg241*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000108 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000494241: "In vitro functional assay demonstrated that this variant resulted in complete loss of phosphatase activity and glycogen binding capacity (Fernandez-Sanchez et al., 2003)."" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: EPM2A NM_005670.4 stop_gained, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 5.66
• Publications: 30 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]

EPM2A Gene-Disease associations (from GenCC):

• Lafora disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000494241: "In vitro functional assay demonstrated that this variant resulted in complete loss of phosphatase activity and glycogen binding capacity (Fernandez-Sanchez et al., 2003)."; SCV005907350: "In vitro functional studies provide some evidence that the p.Arg241Ter variant may slightly impact protein function (PMID: 14532330)."; SCV002673471: "In one in vitro study, this mutation showed loss of phosphatase enzyme activity and also lacked the capacity to bind to glycogen" (Fernández-Sánchez ME et al. Hum. Mol. Genet., 2003 Dec;12:3161-71).
• PP5: Variant 6-145627691-G-A is Pathogenic according to our data. Variant chr6-145627691-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.721C>T	p.Arg241*	stop_gained splice_region	Exon 4 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.721C>T	p.Arg241*	stop_gained splice_region	Exon 4 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001360057.2		c.479C>T	p.Pro160Leu	missense splice_region	Exon 3 of 3	NP_001346986.1	O95278-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.721C>T	p.Arg241*	stop_gained splice_region	Exon 4 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.721C>T	p.Arg241*	stop_gained splice_region	Exon 4 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.479C>T	p.Pro160Leu	missense splice_region	Exon 3 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000766 AC: 19 AN: 247882 AF XY: 0.0000893

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000993

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1461590 Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 80 AN XY: 727114

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000157 AC: 7 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111984

Other (OTH) AF: 0.000133 AC: 8 AN: 60372

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000118 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Lafora disease (5)
3	-	-	Myoclonic epilepsy of Lafora 1 (3)
1	-	-	EPM2A-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.49	T
MetaRNN	Pathogenic	0.80	D
PhyloP100		5.7
GERP RS		4.8
Mutation Taster		=4/196	disease causing (ClinVar)

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: rs104893950; hg19: chr6-145948827; COSMIC: COSV62296130;