6-145735363-C-T

Variant names:

• chr6-145735363-C-T
• rs374338349
• NM_005670.4:c.136G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_005670.4(EPM2A):​c.136G>A​(p.Ala46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000673 in 788,066 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (1 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 B:1
• Conservation: PhyloP100: -0.0750
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018208861).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000447 (29/648384) while in subpopulation AMR AF = 0.00226 (9/3988). AF 95% confidence interval is 0.00118. There are 1 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 24. This position passed quality control check.

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.136G>A	p.Ala46Thr	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.136G>A	p.Ala46Thr	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.136G>A	p.Ala46Thr	missense	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.136G>A	p.Ala46Thr	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.136G>A	p.Ala46Thr	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.136G>A	p.Ala46Thr	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.000186 AC: 26 AN: 139548 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000422

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: 0.00

Gnomad OTH AF: 0.000507

GnomAD2 exomes AF: 0.000439 AC: 5 AN: 11398 AF XY: 0.000411

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000447 AC: 29 AN: 648384 Hom.: 1 Cov.: 24 AF XY: 0.0000533 AC XY: 17 AN XY: 318758

African (AFR) AF: 0.000902 AC: 11 AN: 12192

American (AMR) AF: 0.00226 AC: 9 AN: 3988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6166

East Asian (EAS) AF: 0.00 AC: 0 AN: 8634

South Asian (SAS) AF: 0.0000369 AC: 1 AN: 27088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1454

European-Non Finnish (NFE) AF: 0.00000718 AC: 4 AN: 556928

Other (OTH) AF: 0.000170 AC: 4 AN: 23478

GnomAD4 genome AF: 0.000172 AC: 24 AN: 139682 Hom.: 0 Cov.: 32 AF XY: 0.000192 AC XY: 13 AN XY: 67748

African (AFR) AF: 0.000428 AC: 17 AN: 39716

American (AMR) AF: 0.000421 AC: 6 AN: 14246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3256

East Asian (EAS) AF: 0.00 AC: 0 AN: 4050

South Asian (SAS) AF: 0.00 AC: 0 AN: 3834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63434

Other (OTH) AF: 0.000502 AC: 1 AN: 1992

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000291

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.28	N
PhyloP100		-0.075
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.31	N
REVEL	Benign	0.16
Sift	Benign	0.59	T
Sift4G	Benign	0.40	T
Polyphen		0.81	P
Vest4		0.046
MutPred		0.48		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.88
MPC		0.23
ClinPred		0.011	T
GERP RS		2.4
PromoterAI		-0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.23
Mutation Taster		=98/2	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: rs374338349; hg19: chr6-146056499;