rs35230590

Variant names:

• chr6-145686196-C-T
• rs35230590
• NM_005670.4:c.402G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-145686196-C-T
• chr6-145686196-C-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 1P and 17B. PP3 BP6_Very_Strong BP7 BA1

The NM_005670.4(EPM2A):​c.402G>A​(p.Gly134Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,612,596 control chromosomes in the GnomAD database, including 44,761 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3303 hom., cov: 32)
  • Exomes 𝑓: 0.23 (41458 hom.)
• Consequence: EPM2A NM_005670.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.706
• Publications: 12 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)

ENSG00000307801 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• PP3: REVEL computational evidence supports a deleterious effect, 0.732
• BP6: Variant 6-145686196-C-T is Benign according to our data. Variant chr6-145686196-C-T is described in ClinVar as Benign. ClinVar VariationId is 129005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.706 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

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.402G>A	p.Gly134Gly	synonymous	Exon 2 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.402G>A	p.Gly134Gly	synonymous	Exon 2 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.402G>A	p.Gly134Gly	synonymous	Exon 2 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.402G>A	p.Gly134Gly	synonymous	Exon 2 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.402G>A	p.Gly134Gly	synonymous	Exon 2 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.402G>A	p.Gly134Gly	synonymous	Exon 2 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27793 AN: 151958 Hom.: 3304 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.214 AC: 53770 AN: 251320 AF XY: 0.210

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.00827

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.230 AC: 335864 AN: 1460518 Hom.: 41458 Cov.: 33 AF XY: 0.228 AC XY: 165746 AN XY: 726626

African (AFR) AF: 0.0356 AC: 1193 AN: 33468

American (AMR) AF: 0.352 AC: 15736 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6614 AN: 26122

East Asian (EAS) AF: 0.00509 AC: 202 AN: 39684

South Asian (SAS) AF: 0.163 AC: 14075 AN: 86240

European-Finnish (FIN) AF: 0.225 AC: 12010 AN: 53408

Middle Eastern (MID) AF: 0.124 AC: 715 AN: 5766

European-Non Finnish (NFE) AF: 0.246 AC: 272805 AN: 1110816

Other (OTH) AF: 0.207 AC: 12514 AN: 60340

GnomAD4 genome AF: 0.183 AC: 27795 AN: 152078 Hom.: 3303 Cov.: 32 AF XY: 0.180 AC XY: 13395 AN XY: 74336

African (AFR) AF: 0.0449 AC: 1865 AN: 41516

American (AMR) AF: 0.284 AC: 4330 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 880 AN: 3470

East Asian (EAS) AF: 0.00810 AC: 42 AN: 5182

South Asian (SAS) AF: 0.164 AC: 791 AN: 4822

European-Finnish (FIN) AF: 0.226 AC: 2387 AN: 10556

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16630 AN: 67954

Other (OTH) AF: 0.179 AC: 379 AN: 2114

Alfa AF: 0.182 Hom.: 2521

Bravo AF: 0.181

Asia WGS AF: 0.100 AC: 352 AN: 3478

EpiCase AF: 0.229

EpiControl AF: 0.227

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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
BayesDel_noAF	Benign	-0.34
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.71
PromoterAI		0.036	Neutral
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35230590; hg19: chr6-146007332; COSMIC: COSV62296292;