6-145735340-G-C

Variant names:

• chr6-145735340-G-C
• rs2235482
• NM_005670.4:c.159C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005670.4(EPM2A):​c.159C>G​(p.Ala53Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 1,386,774 control chromosomes in the GnomAD database, including 246,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A53A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.63 (30260 hom., cov: 31)
  • Exomes 𝑓: 0.59 (216486 hom.)
• Consequence: EPM2A NM_005670.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.643
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-145735340-G-C is Benign according to our data. Variant chr6-145735340-G-C is described in ClinVar as Benign. ClinVar VariationId is 95306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.643 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 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.159C>G	p.Ala53Ala	synonymous	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.159C>G	p.Ala53Ala	synonymous	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.159C>G	p.Ala53Ala	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.159C>G	p.Ala53Ala	synonymous	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.159C>G	p.Ala53Ala	synonymous	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.159C>G	p.Ala53Ala	synonymous	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.631 AC: 94339 AN: 149600 Hom.: 30225 Cov.: 31

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.643

GnomAD2 exomes AF: 0.614 AC: 46781 AN: 76174 AF XY: 0.591

Gnomad AFR exome AF: 0.687

Gnomad AMR exome AF: 0.804

Gnomad ASJ exome AF: 0.628

Gnomad EAS exome AF: 0.764

Gnomad FIN exome AF: 0.528

Gnomad NFE exome AF: 0.588

Gnomad OTH exome AF: 0.622

GnomAD4 exome AF: 0.589 AC: 728552 AN: 1237064 Hom.: 216486 Cov.: 35 AF XY: 0.585 AC XY: 355979 AN XY: 608792

African (AFR) AF: 0.706 AC: 17623 AN: 24958

American (AMR) AF: 0.778 AC: 18554 AN: 23860

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 12265 AN: 20072

East Asian (EAS) AF: 0.727 AC: 17584 AN: 24180

South Asian (SAS) AF: 0.476 AC: 30429 AN: 63978

European-Finnish (FIN) AF: 0.522 AC: 16086 AN: 30802

Middle Eastern (MID) AF: 0.595 AC: 2191 AN: 3680

European-Non Finnish (NFE) AF: 0.587 AC: 584416 AN: 996356

Other (OTH) AF: 0.598 AC: 29404 AN: 49178

GnomAD4 genome AF: 0.631 AC: 94416 AN: 149710 Hom.: 30260 Cov.: 31 AF XY: 0.627 AC XY: 45811 AN XY: 73052

African (AFR) AF: 0.708 AC: 29212 AN: 41236

American (AMR) AF: 0.714 AC: 10774 AN: 15094

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2108 AN: 3428

East Asian (EAS) AF: 0.741 AC: 3740 AN: 5044

South Asian (SAS) AF: 0.486 AC: 2341 AN: 4820

European-Finnish (FIN) AF: 0.504 AC: 4891 AN: 9710

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.586 AC: 39291 AN: 67106

Other (OTH) AF: 0.638 AC: 1321 AN: 2072

Alfa AF: 0.507 Hom.: 1432

Bravo AF: 0.653

Asia WGS AF: 0.567 AC: 1844 AN: 3250

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Lafora disease (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.3
DANN	Benign	0.63
PhyloP100		-0.64
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs2235482; hg19: chr6-146056476; COSMIC: COSV62294993; COSMIC: COSV62294993;