rs142027344

Variant names:

• chr6-145627563-A-G
• rs142027344
• ENST00000638262.1:c.607T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_001360057.2(EPM2A):​c.607T>C​(p.Cys203Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,614,244 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: EPM2A NM_001360057.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.330
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07001069).
• BP6: Variant 6-145627563-A-G is Benign according to our data. Variant chr6-145627563-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000329 (481/1461890) while in subpopulation MID AF = 0.00312 (18/5768). AF 95% confidence interval is 0.00202. There are 1 homozygotes in GnomAdExome4. There are 221 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360057.2. 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.849T>C	p.Tyr283Tyr	synonymous	Exon 4 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360057.2		c.607T>C	p.Cys203Arg	missense	Exon 3 of 3	NP_001346986.1	O95278-5
	EPM2A	NM_001018041.2		c.849T>C	p.Tyr283Tyr	synonymous	Exon 4 of 5	NP_001018051.1	O95278-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000638262.1	TSL:1	c.607T>C	p.Cys203Arg	missense	Exon 3 of 3	ENSP00000492876.1	O95278-5
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.849T>C	p.Tyr283Tyr	synonymous	Exon 4 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.849T>C	p.Tyr283Tyr	synonymous	Exon 4 of 5	ENSP00000405913.2	O95278-2

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000312 AC: 78 AN: 250262 AF XY: 0.000288

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000329 AC: 481 AN: 1461890 Hom.: 1 Cov.: 32 AF XY: 0.000304 AC XY: 221 AN XY: 727246

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000294 AC: 327 AN: 1112010

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74508

African (AFR) AF: 0.000337 AC: 14 AN: 41590

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.38
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.070	T
PhyloP100		0.33
GERP RS		-5.1
Mutation Taster		=99/1	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: rs142027344; hg19: chr6-145948699;