rs117055625

Variant names:

• chr6-145625446-A-G
• rs117055625
• NM_005670.4:c.*1970T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005670.4(EPM2A):​c.*1970T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 489,442 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 33)
  • Exomes 𝑓: 0.012 (39 hom.)
• Consequence: EPM2A NM_005670.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.562
• 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-145625446-A-G is Benign according to our data. Variant chr6-145625446-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1197768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0108 (1649/152344) while in subpopulation AMR AF = 0.0175 (268/15312). AF 95% confidence interval is 0.0158. There are 13 homozygotes in GnomAd4. There are 766 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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.*1970T>C		3_prime_UTR	Exon 4 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.*249T>C		3_prime_UTR	Exon 5 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001360057.2		c.*2049T>C		3_prime_UTR	Exon 3 of 3	NP_001346986.1	O95278-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.*1970T>C		3_prime_UTR	Exon 4 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.*249T>C		3_prime_UTR	Exon 5 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000639423.1	TSL:1	c.*1970T>C		3_prime_UTR	Exon 4 of 4	ENSP00000492701.1	O95278-8

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1641 AN: 152226 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0124 AC: 4183 AN: 337098 Hom.: 39 Cov.: 0 AF XY: 0.0125 AC XY: 2215 AN XY: 177376

African (AFR) AF: 0.00887 AC: 94 AN: 10594

American (AMR) AF: 0.0183 AC: 265 AN: 14444

Ashkenazi Jewish (ASJ) AF: 0.00320 AC: 34 AN: 10626

East Asian (EAS) AF: 0.00152 AC: 37 AN: 24400

South Asian (SAS) AF: 0.0130 AC: 402 AN: 30824

European-Finnish (FIN) AF: 0.00514 AC: 95 AN: 18492

Middle Eastern (MID) AF: 0.0115 AC: 17 AN: 1484

European-Non Finnish (NFE) AF: 0.0144 AC: 2966 AN: 206342

Other (OTH) AF: 0.0137 AC: 273 AN: 19892

GnomAD4 genome AF: 0.0108 AC: 1649 AN: 152344 Hom.: 13 Cov.: 33 AF XY: 0.0103 AC XY: 766 AN XY: 74500

African (AFR) AF: 0.00712 AC: 296 AN: 41584

American (AMR) AF: 0.0175 AC: 268 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5182

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4830

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 935 AN: 68024

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0118 Hom.: 2

Bravo AF: 0.0120

Asia WGS AF: 0.0140 AC: 49 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.13
DANN	Benign	0.54
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism

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: rs117055625; hg19: chr6-145946582;