NM_005670.4:c.314A>G

Variant names:

• chr6-145686284-T-C
• rs1554263366
• NM_005670.4:c.314A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_005670.4(EPM2A):​c.314A>G​(p.His105Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.81
• 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

ENSG00000307801 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005670.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-145686284-T-C is Pathogenic according to our data. Variant chr6-145686284-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 433103.Status of the report is no_assertion_criteria_provided, 0 stars.

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.314A>G	p.His105Arg	missense	Exon 2 of 4	NP_005661.1
	EPM2A	NM_001018041.2		c.314A>G	p.His105Arg	missense	Exon 2 of 5	NP_001018051.1
	EPM2A	NM_001368130.1		c.314A>G	p.His105Arg	missense	Exon 2 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.314A>G	p.His105Arg	missense	Exon 2 of 4	ENSP00000356489.3
	EPM2A	ENST00000435470.2	TSL:1	c.314A>G	p.His105Arg	missense	Exon 2 of 5	ENSP00000405913.2
	EPM2A	ENST00000638262.1	TSL:1	c.314A>G	p.His105Arg	missense	Exon 2 of 3	ENSP00000492876.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.64
Sift	Benign	0.28	T
Sift4G	Benign	0.21	T
Polyphen		0.86	P
Vest4		0.58
MutPred		0.52		Gain of solvent accessibility (P = 0.0704)
MVP		0.96
MPC		0.68
ClinPred		0.87	D
GERP RS		4.7
PromoterAI		0.055	Neutral
gMVP		0.64
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554263366; hg19: chr6-146007420;