rs1045820

Variant names:

• chr6-145625944-C-T
• rs1045820
• NM_005670.4:c.*1472G>A

Variant summary

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

The NM_005670.4(EPM2A):​c.*1472G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 1,291,750 control chromosomes in the GnomAD database, including 123,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (16539 hom., cov: 32)
  • Exomes 𝑓: 0.43 (107297 hom.)
• Consequence: EPM2A NM_005670.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.36
• 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: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 6-145625944-C-T is Benign according to our data. Variant chr6-145625944-C-T is described in ClinVar as Benign. ClinVar VariationId is 1230296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.545 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	NM_005670.4	MANE Select	c.*1472G>A		3_prime_UTR	Exon 4 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360057.2		c.*1551G>A		3_prime_UTR	Exon 3 of 3	NP_001346986.1	O95278-5
	EPM2A	NM_001360064.2		c.*1472G>A		3_prime_UTR	Exon 4 of 4	NP_001346993.1	O95278-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.*1472G>A		3_prime_UTR	Exon 4 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000638262.1	TSL:1	c.*1551G>A		3_prime_UTR	Exon 3 of 3	ENSP00000492876.1	O95278-5
	EPM2A	ENST00000639423.1	TSL:1	c.*1472G>A		3_prime_UTR	Exon 4 of 4	ENSP00000492701.1	O95278-8

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69701 AN: 151904 Hom.: 16513 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.446

GnomAD4 exome AF: 0.429 AC: 489474 AN: 1139728 Hom.: 107297 Cov.: 14 AF XY: 0.432 AC XY: 240347 AN XY: 556338

African (AFR) AF: 0.565 AC: 14381 AN: 25470

American (AMR) AF: 0.296 AC: 5697 AN: 19262

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 7000 AN: 17644

East Asian (EAS) AF: 0.328 AC: 10906 AN: 33224

South Asian (SAS) AF: 0.536 AC: 28914 AN: 53986

European-Finnish (FIN) AF: 0.491 AC: 13609 AN: 27728

Middle Eastern (MID) AF: 0.437 AC: 2123 AN: 4862

European-Non Finnish (NFE) AF: 0.424 AC: 386038 AN: 909400

Other (OTH) AF: 0.432 AC: 20806 AN: 48152

GnomAD4 genome AF: 0.459 AC: 69772 AN: 152022 Hom.: 16539 Cov.: 32 AF XY: 0.461 AC XY: 34248 AN XY: 74306

African (AFR) AF: 0.551 AC: 22837 AN: 41462

American (AMR) AF: 0.345 AC: 5271 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1361 AN: 3472

East Asian (EAS) AF: 0.330 AC: 1708 AN: 5170

South Asian (SAS) AF: 0.534 AC: 2570 AN: 4816

European-Finnish (FIN) AF: 0.510 AC: 5381 AN: 10546

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29218 AN: 67964

Other (OTH) AF: 0.453 AC: 954 AN: 2108

Alfa AF: 0.434 Hom.: 3545

Bravo AF: 0.450

Asia WGS AF: 0.476 AC: 1655 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.085
DANN	Benign	0.30
PhyloP100		-1.4
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: rs1045820; hg19: chr6-145947080; COSMIC: COSV62295394; COSMIC: COSV62295394;