rs370653

Variant names:

• chr6-145502506-G-A
• rs370653
• ENST00000638717.1:c.553+16C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000450221.6(EPM2A):​c.394+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 468,968 control chromosomes in the GnomAD database, including 52,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (15466 hom., cov: 32)
  • Exomes 𝑓: 0.48 (37189 hom.)
• Consequence: EPM2A ENST00000450221.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.753
• 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-145502506-G-A is Benign according to our data. Variant chr6-145502506-G-A is described in ClinVar as Benign. ClinVar VariationId is 3255263.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000450221.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000638717.1	TSL:5	c.553+16C>T		intron	N/A	ENSP00000491330.1	A0A1W2PPT8
	EPM2A	ENST00000450221.6	TSL:3	c.394+16C>T		intron	N/A	ENSP00000414900.2	H0Y7S8

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68434 AN: 151962 Hom.: 15443 Cov.: 32

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.441

GnomAD2 exomes AF: 0.469 AC: 68494 AN: 145920 AF XY: 0.479

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.512

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.462

GnomAD4 exome AF: 0.479 AC: 151869 AN: 316888 Hom.: 37189 Cov.: 0 AF XY: 0.490 AC XY: 87730 AN XY: 179190

African (AFR) AF: 0.420 AC: 3600 AN: 8566

American (AMR) AF: 0.402 AC: 10953 AN: 27248

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 4857 AN: 10782

East Asian (EAS) AF: 0.417 AC: 3835 AN: 9190

South Asian (SAS) AF: 0.577 AC: 34386 AN: 59630

European-Finnish (FIN) AF: 0.512 AC: 13696 AN: 26770

Middle Eastern (MID) AF: 0.472 AC: 800 AN: 1696

European-Non Finnish (NFE) AF: 0.460 AC: 73053 AN: 158834

Other (OTH) AF: 0.472 AC: 6689 AN: 14172

GnomAD4 genome AF: 0.450 AC: 68501 AN: 152080 Hom.: 15466 Cov.: 32 AF XY: 0.456 AC XY: 33884 AN XY: 74320

African (AFR) AF: 0.413 AC: 17152 AN: 41484

American (AMR) AF: 0.413 AC: 6308 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1579 AN: 3466

East Asian (EAS) AF: 0.427 AC: 2204 AN: 5164

South Asian (SAS) AF: 0.584 AC: 2817 AN: 4824

European-Finnish (FIN) AF: 0.519 AC: 5483 AN: 10572

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

European-Non Finnish (NFE) AF: 0.463 AC: 31460 AN: 67976

Other (OTH) AF: 0.447 AC: 945 AN: 2114

Alfa AF: 0.443 Hom.: 2805

Bravo AF: 0.438

Asia WGS AF: 0.533 AC: 1851 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.1
DANN	Benign	0.49
PhyloP100		0.75

Splicing

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

Other links and lift over

dbSNP: rs370653; hg19: chr6-145823642;