NM_005670.4:c.*1731G>A

Variant names:

• chr6-145625685-C-T
• rs752896079
• NM_005670.4:c.*1731G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_005670.4(EPM2A):​c.*1731G>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 0.00000657 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPM2A NM_005670.4 3_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.156
• 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, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-145625685-C-T is Benign according to our data. Variant chr6-145625685-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3053538.Status of the report is no_assertion_criteria_provided, 0 stars.

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.*1731G>A		3_prime_UTR	Exon 4 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.*10G>A		3_prime_UTR	Exon 5 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001360057.2		c.*1810G>A		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.*1731G>A		3_prime_UTR	Exon 4 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.*10G>A		3_prime_UTR	Exon 5 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.*1810G>A		3_prime_UTR	Exon 3 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000462 AC: 1 AN: 216278 AF XY: 0.00000863

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 617892 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 334638

African (AFR) AF: 0.00 AC: 0 AN: 17420

American (AMR) AF: 0.00 AC: 0 AN: 40740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20618

East Asian (EAS) AF: 0.00 AC: 0 AN: 35420

South Asian (SAS) AF: 0.00 AC: 0 AN: 66084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 348940

Other (OTH) AF: 0.00 AC: 0 AN: 32644

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EPM2A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.8
DANN	Benign	0.65
PhyloP100		0.16

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: rs752896079; hg19: chr6-145946821;