rs187930476

Variant names:

• chr6-145735336-G-A
• rs187930476
• NM_005670.4:c.163C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-145735336-G-A
• chr6-145735336-G-T
• chr6-145735336-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005670.4(EPM2A):​c.163C>T​(p.Gln55*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000239 in 1,383,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: EPM2A NM_005670.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.35
• Publications: 11 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-145735336-G-A is Pathogenic according to our data. Variant chr6-145735336-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 419335.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.163C>T	p.Gln55*	stop_gained	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.163C>T	p.Gln55*	stop_gained	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.163C>T	p.Gln55*	stop_gained	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.163C>T	p.Gln55*	stop_gained	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.163C>T	p.Gln55*	stop_gained	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.163C>T	p.Gln55*	stop_gained	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000872

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000644 AC: 5 AN: 77612 AF XY: 0.0000224

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000769

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 30 AN: 1232942 Hom.: 0 Cov.: 30 AF XY: 0.0000148 AC XY: 9 AN XY: 607692

African (AFR) AF: 0.00 AC: 0 AN: 24162

American (AMR) AF: 0.0000427 AC: 1 AN: 23396

Ashkenazi Jewish (ASJ) AF: 0.00102 AC: 20 AN: 19586

East Asian (EAS) AF: 0.00 AC: 0 AN: 22680

South Asian (SAS) AF: 0.00 AC: 0 AN: 67368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3746

European-Non Finnish (NFE) AF: 0.00000705 AC: 7 AN: 993390

Other (OTH) AF: 0.0000411 AC: 2 AN: 48620

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 150160 Hom.: 0 Cov.: 32 AF XY: 0.0000409 AC XY: 3 AN XY: 73278

African (AFR) AF: 0.00 AC: 0 AN: 41210

American (AMR) AF: 0.00 AC: 0 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.000872 AC: 3 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67342

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 3

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Myoclonic epilepsy of Lafora 1 (2)
1	-	-	Lafora disease (1)
1	-	-	not provided (1)
1	-	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		4.4
Vest4		0.71
GERP RS		3.5
PromoterAI		0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=1/199	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: rs187930476; hg19: chr6-146056472;