chr6-145735328-C-G

Variant names:

• chr6-145735328-C-G
• rs531330673
• NM_005670.4:c.171G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_005670.4(EPM2A):​c.171G>C​(p.Pro57Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000844 in 1,304,042 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 (★). Synonymous variant affecting the same amino acid position (i.e. P57P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: EPM2A NM_005670.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.497
• Publications: 1 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]

ENSG00000288551 (HGNC:):

EPM2A-DT (HGNC:48990): (EPM2A divergent transcript)

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=-0.46).
• BP6: Variant 6-145735328-C-G is Benign according to our data. Variant chr6-145735328-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2163978.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.497 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	NM_005670.4	MANE Select	c.171G>C	p.Pro57Pro	synonymous	Exon 1 of 4	NP_005661.1
	EPM2A	NM_001018041.2		c.171G>C	p.Pro57Pro	synonymous	Exon 1 of 5	NP_001018051.1
	EPM2A	NM_001368130.1		c.171G>C	p.Pro57Pro	synonymous	Exon 1 of 3	NP_001355059.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.171G>C	p.Pro57Pro	synonymous	Exon 1 of 4	ENSP00000356489.3
	EPM2A	ENST00000435470.2	TSL:1	c.171G>C	p.Pro57Pro	synonymous	Exon 1 of 5	ENSP00000405913.2
	EPM2A	ENST00000638262.1	TSL:1	c.171G>C	p.Pro57Pro	synonymous	Exon 1 of 3	ENSP00000492876.1

Frequencies

GnomAD3 genomes AF: 0.0000203 AC: 3 AN: 147686 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000408

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000692 AC: 8 AN: 1156230 Hom.: 0 Cov.: 30 AF XY: 0.00000528 AC XY: 3 AN XY: 568576

African (AFR) AF: 0.00 AC: 0 AN: 22122

American (AMR) AF: 0.00 AC: 0 AN: 22716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16710

East Asian (EAS) AF: 0.00 AC: 0 AN: 15678

South Asian (SAS) AF: 0.00 AC: 0 AN: 69882

European-Finnish (FIN) AF: 0.0000847 AC: 2 AN: 23608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3506

European-Non Finnish (NFE) AF: 0.00000639 AC: 6 AN: 938586

Other (OTH) AF: 0.00 AC: 0 AN: 43422

GnomAD4 genome AF: 0.0000203 AC: 3 AN: 147812 Hom.: 0 Cov.: 32 AF XY: 0.0000416 AC XY: 3 AN XY: 72134

African (AFR) AF: 0.00 AC: 0 AN: 40988

American (AMR) AF: 0.00 AC: 0 AN: 14918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.000409 AC: 2 AN: 4890

South Asian (SAS) AF: 0.00 AC: 0 AN: 4472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66502

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.4
DANN	Benign	0.66
PhyloP100		-0.50
PromoterAI		-0.089	Neutral
Mutation Taster		=99/1	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: rs531330673; hg19: chr6-146056464;