6-145735291-C-G

Variant names:

• chr6-145735291-C-G
• rs550455609
• NM_005670.4:c.208G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_005670.4(EPM2A):​c.208G>C​(p.Glu70Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,484,874 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. E70V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.09
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03954661).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000311 (47/151106) while in subpopulation AMR AF = 0.00171 (26/15202). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.208G>C	p.Glu70Gln	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.208G>C	p.Glu70Gln	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.208G>C	p.Glu70Gln	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.208G>C	p.Glu70Gln	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.208G>C	p.Glu70Gln	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.208G>C	p.Glu70Gln	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.000311 AC: 47 AN: 151000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

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: 0.000267

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000269 AC: 28 AN: 103996 AF XY: 0.000190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000460

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.000675

GnomAD4 exome AF: 0.000207 AC: 276 AN: 1333768 Hom.: 1 Cov.: 30 AF XY: 0.000207 AC XY: 136 AN XY: 658398

African (AFR) AF: 0.0000371 AC: 1 AN: 26982

American (AMR) AF: 0.000755 AC: 23 AN: 30474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22886

East Asian (EAS) AF: 0.00 AC: 0 AN: 29188

South Asian (SAS) AF: 0.00 AC: 0 AN: 74920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5118

European-Non Finnish (NFE) AF: 0.000224 AC: 235 AN: 1048380

Other (OTH) AF: 0.000312 AC: 17 AN: 54456

GnomAD4 genome AF: 0.000311 AC: 47 AN: 151106 Hom.: 0 Cov.: 32 AF XY: 0.000325 AC XY: 24 AN XY: 73830

African (AFR) AF: 0.0000724 AC: 3 AN: 41430

American (AMR) AF: 0.00171 AC: 26 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000267 AC: 18 AN: 67526

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000731 Hom.: 0

Bravo AF: 0.000468

ExAC AF: 0.0000623 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	15
DANN	Benign	0.75
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.040	T
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.24
Sift	Benign	0.080	T
Sift4G	Benign	0.30	T
Polyphen		0.99	D
Vest4		0.046
MutPred		0.36		Loss of helix (P = 0.0167)
MVP		0.94
MPC		0.24
ClinPred		0.11	T
GERP RS		2.6
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
gMVP		0.44
Mutation Taster		=86/14	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: rs550455609; hg19: chr6-146056427;