6-145701395-T-C

Variant names:

• chr6-145701395-T-C
• rs1415744
• NM_005670.4:c.302-15099A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005670.4(EPM2A):​c.302-15099A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 152,054 control chromosomes in the GnomAD database, including 23,158 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (23158 hom., cov: 32)
• Consequence: EPM2A NM_005670.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.829
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

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.302-15099A>G		intron	N/A	NP_005661.1
	EPM2A	NM_001018041.2		c.302-15099A>G		intron	N/A	NP_001018051.1
	EPM2A	NM_001368130.1		c.302-15099A>G		intron	N/A	NP_001355059.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.302-15099A>G		intron	N/A	ENSP00000356489.3
	EPM2A	ENST00000435470.2	TSL:1	c.302-15099A>G		intron	N/A	ENSP00000405913.2
	EPM2A	ENST00000638262.1	TSL:1	c.302-15099A>G		intron	N/A	ENSP00000492876.1

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82809 AN: 151936 Hom.: 23141 Cov.: 32

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.560

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.545 AC: 82862 AN: 152054 Hom.: 23158 Cov.: 32 AF XY: 0.544 AC XY: 40400 AN XY: 74296

African (AFR) AF: 0.449 AC: 18620 AN: 41462

American (AMR) AF: 0.656 AC: 10026 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2113 AN: 3466

East Asian (EAS) AF: 0.740 AC: 3821 AN: 5164

South Asian (SAS) AF: 0.474 AC: 2285 AN: 4824

European-Finnish (FIN) AF: 0.504 AC: 5325 AN: 10566

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38769 AN: 67972

Other (OTH) AF: 0.556 AC: 1171 AN: 2108

Alfa AF: 0.569 Hom.: 8262

Bravo AF: 0.554

Asia WGS AF: 0.564 AC: 1961 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.7
DANN	Benign	0.41
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism (auto)

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: rs1415744; hg19: chr6-146022531;