rs547147183

Variant names:

• chr6-145735370-G-C
• rs547147183
• NM_005670.4:c.129C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-145735370-G-C
• chr6-145735370-G-A
• chr6-145735370-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_005670.4(EPM2A):​c.129C>G​(p.Ala43Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,250,822 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: EPM2A NM_005670.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.00100
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 6-145735370-G-C is Benign according to our data. Variant chr6-145735370-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137223.
• BP7: Synonymous conserved (PhyloP=-0.001 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00132 (197/149498) while in subpopulation AFR AF = 0.00446 (184/41230). AF 95% confidence interval is 0.00394. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.129C>G	p.Ala43Ala	synonymous	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.129C>G	p.Ala43Ala	synonymous	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.129C>G	p.Ala43Ala	synonymous	Exon 1 of 3	NP_001355059.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.129C>G	p.Ala43Ala	synonymous	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.129C>G	p.Ala43Ala	synonymous	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.129C>G	p.Ala43Ala	synonymous	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 196 AN: 149400 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00445

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000399

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: 0.0000896

Gnomad OTH AF: 0.000485

GnomAD2 exomes AF: 0.000176 AC: 2 AN: 11338 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 117 AN: 1101324 Hom.: 0 Cov.: 36 AF XY: 0.000101 AC XY: 54 AN XY: 533180

African (AFR) AF: 0.00358 AC: 77 AN: 21534

American (AMR) AF: 0.000343 AC: 3 AN: 8740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13214

East Asian (EAS) AF: 0.00 AC: 0 AN: 22096

South Asian (SAS) AF: 0.0000296 AC: 1 AN: 33788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22198

Middle Eastern (MID) AF: 0.00104 AC: 3 AN: 2880

European-Non Finnish (NFE) AF: 0.0000182 AC: 17 AN: 934156

Other (OTH) AF: 0.000375 AC: 16 AN: 42718

GnomAD4 genome AF: 0.00132 AC: 197 AN: 149498 Hom.: 0 Cov.: 33 AF XY: 0.00130 AC XY: 95 AN XY: 72974

African (AFR) AF: 0.00446 AC: 184 AN: 41230

American (AMR) AF: 0.000399 AC: 6 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000896 AC: 6 AN: 66988

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.00126

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
-	-	1	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.3
DANN	Benign	0.32
PhyloP100		-0.0010
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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: rs547147183; hg19: chr6-146056506;