6-145735336-G-C

Variant names:

• chr6-145735336-G-C
• rs187930476
• NM_005670.4:c.163C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005670.4(EPM2A):​c.163C>G​(p.Gln55Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000217 in 1,383,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q55P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.35
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25504282).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	NM_005670.4	MANE Select	c.163C>G	p.Gln55Glu	missense	Exon 1 of 4	NP_005661.1
	EPM2A	NM_001018041.2		c.163C>G	p.Gln55Glu	missense	Exon 1 of 5	NP_001018051.1
	EPM2A	NM_001368130.1		c.163C>G	p.Gln55Glu	missense	Exon 1 of 3	NP_001355059.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.163C>G	p.Gln55Glu	missense	Exon 1 of 4	ENSP00000356489.3
	EPM2A	ENST00000435470.2	TSL:1	c.163C>G	p.Gln55Glu	missense	Exon 1 of 5	ENSP00000405913.2
	EPM2A	ENST00000638262.1	TSL:1	c.163C>G	p.Gln55Glu	missense	Exon 1 of 3	ENSP00000492876.1

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000162 AC: 2 AN: 1232942 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 607692

African (AFR) AF: 0.00 AC: 0 AN: 24162

American (AMR) AF: 0.00 AC: 0 AN: 23396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19586

East Asian (EAS) AF: 0.00 AC: 0 AN: 22680

South Asian (SAS) AF: 0.00 AC: 0 AN: 67368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3746

European-Non Finnish (NFE) AF: 0.00000201 AC: 2 AN: 993390

Other (OTH) AF: 0.00 AC: 0 AN: 48620

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73278

African (AFR) AF: 0.00 AC: 0 AN: 41210

American (AMR) AF: 0.00 AC: 0 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67342

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Benign	0.66
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.21	N
REVEL	Benign	0.26
Sift	Benign	0.82	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.38		Gain of disorder (P = 0.0619)
MVP		0.95
MPC		0.26
ClinPred		0.17	T
GERP RS		3.5
PromoterAI		0.069	Neutral
gMVP		0.30
Mutation Taster		=95/5	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: rs187930476; hg19: chr6-146056472;