rs150452237

Variant names:

• chr6-145686222-T-C
• rs150452237
• NM_005670.4:c.376A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005670.4(EPM2A):​c.376A>G​(p.Ile126Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,613,832 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I126T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (8 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.883
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007952094).
• BP6: Variant 6-145686222-T-C is Benign according to our data. Variant chr6-145686222-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167038.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000515 (752/1461524) while in subpopulation MID AF = 0.00277 (16/5768). AF 95% confidence interval is 0.00174. There are 8 homozygotes in GnomAdExome4. There are 418 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

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.376A>G	p.Ile126Val	missense	Exon 2 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.376A>G	p.Ile126Val	missense	Exon 2 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.376A>G	p.Ile126Val	missense	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.376A>G	p.Ile126Val	missense	Exon 2 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.376A>G	p.Ile126Val	missense	Exon 2 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.376A>G	p.Ile126Val	missense	Exon 2 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000867 AC: 218 AN: 251418 AF XY: 0.000949

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000515 AC: 752 AN: 1461524 Hom.: 8 Cov.: 32 AF XY: 0.000575 AC XY: 418 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000201 AC: 9 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 297 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.00176 AC: 152 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000187 AC: 208 AN: 1111718

Other (OTH) AF: 0.00113 AC: 68 AN: 60386

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74472

African (AFR) AF: 0.0000962 AC: 4 AN: 41572

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000781 Hom.: 2

Bravo AF: 0.000499

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Cataract;C1837397:Severe global developmental delay;C4551563:Microcephaly (1)
-	-	1	EPM2A-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.70
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.88
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.25
Sift	Benign	0.72	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.76
MPC		0.20
ClinPred		0.0014	T
GERP RS		1.8
PromoterAI		-0.0020	Neutral
gMVP		0.39
Mutation Taster		=94/6	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: rs150452237; hg19: chr6-146007358;