6-145627587-C-A

Variant names:

• chr6-145627587-C-A
• rs762115387
• ENST00000638262.1:c.583G>T

Variant summary

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

The ENST00000638262.1(EPM2A):​c.583G>T​(p.Gly195Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/12 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. G195S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPM2A ENST00000638262.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42
• 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]

EPM2A Gene-Disease associations (from GenCC):

• Lafora disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia

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=0.23441714).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000638262.1. 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.825G>T	p.Ala275Ala	synonymous	Exon 4 of 4	NP_005661.1
	EPM2A	NM_001360057.2		c.583G>T	p.Gly195Cys	missense	Exon 3 of 3	NP_001346986.1
	EPM2A	NM_001018041.2		c.825G>T	p.Ala275Ala	synonymous	Exon 4 of 5	NP_001018051.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000638262.1	TSL:1	c.583G>T	p.Gly195Cys	missense	Exon 3 of 3	ENSP00000492876.1
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.825G>T	p.Ala275Ala	synonymous	Exon 4 of 4	ENSP00000356489.3
	EPM2A	ENST00000435470.2	TSL:1	c.825G>T	p.Ala275Ala	synonymous	Exon 4 of 5	ENSP00000405913.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.11
DANN	Benign	0.64
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.23	T
PhyloP100		-2.4
GERP RS		-6.3
Mutation Taster		=96/4	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: rs762115387; hg19: chr6-145948723;