6-145547860-C-T

Variant names:

• chr6-145547860-C-T
• rs447818
• ENST00000638717.1:c.500-45285G>A

Variant summary

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

The ENST00000638717.1(EPM2A):​c.500-45285G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,728 control chromosomes in the GnomAD database, including 15,968 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 0.46 (15968 hom., cov: 33)
• Consequence: EPM2A ENST00000638717.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	XM_024446550.2	c.719-45285G>A		intron_variant	Intron 3 of 4		XP_024302318.1
EPM2A	XM_011536113.3	c.719-45285G>A		intron_variant	Intron 3 of 4		XP_011534415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000638717.1	c.500-45285G>A		intron_variant	Intron 3 of 4	5		ENSP00000491330.1
EPM2A	ENST00000450221.6	c.341-45285G>A		intron_variant	Intron 2 of 3	3		ENSP00000414900.2

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69585 AN: 151610 Hom.: 15934 Cov.: 33

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.446

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

GnomAD4 genome AF: 0.459 AC: 69670 AN: 151728 Hom.: 15968 Cov.: 33 AF XY: 0.466 AC XY: 34502 AN XY: 74108

African (AFR) AF: 0.443 AC: 18347 AN: 41412

American (AMR) AF: 0.414 AC: 6314 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 1533 AN: 3462

East Asian (EAS) AF: 0.514 AC: 2639 AN: 5138

South Asian (SAS) AF: 0.593 AC: 2855 AN: 4814

European-Finnish (FIN) AF: 0.526 AC: 5524 AN: 10504

Middle Eastern (MID) AF: 0.507 AC: 148 AN: 292

European-Non Finnish (NFE) AF: 0.457 AC: 31016 AN: 67838

Other (OTH) AF: 0.453 AC: 953 AN: 2104

Alfa AF: 0.446 Hom.: 5678

Bravo AF: 0.449

Asia WGS AF: 0.571 AC: 1985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.57
PhyloP100		-0.24

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs447818; hg19: chr6-145868996;