6-145735475-C-T

Variant names:

• chr6-145735475-C-T
• rs587780938
• NM_005670.4:c.24G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_005670.4(EPM2A):​c.24G>A​(p.Val8Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,212,804 control chromosomes in the GnomAD database, including 4 homozygotes. 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 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: EPM2A NM_005670.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.369
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 6-145735475-C-T is Benign according to our data. Variant chr6-145735475-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137222.
• BP7: Synonymous conserved (PhyloP=0.369 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000772 (117/151584) while in subpopulation NFE AF = 0.0014 (95/67762). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.24G>A	p.Val8Val	synonymous	Exon 1 of 4	NP_005661.1
	EPM2A	NM_001018041.2		c.24G>A	p.Val8Val	synonymous	Exon 1 of 5	NP_001018051.1
	EPM2A	NM_001368130.1		c.24G>A	p.Val8Val	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.24G>A	p.Val8Val	synonymous	Exon 1 of 4	ENSP00000356489.3
	EPM2A	ENST00000435470.2	TSL:1	c.24G>A	p.Val8Val	synonymous	Exon 1 of 5	ENSP00000405913.2
	EPM2A	ENST00000638262.1	TSL:1	c.24G>A	p.Val8Val	synonymous	Exon 1 of 3	ENSP00000492876.1

Frequencies

GnomAD3 genomes AF: 0.000772 AC: 117 AN: 151476 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

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: 0.00140

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000551 AC: 3 AN: 5446 AF XY: 0.000614

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: 0.00153

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00159 AC: 1691 AN: 1061220 Hom.: 4 Cov.: 34 AF XY: 0.00155 AC XY: 787 AN XY: 506852

African (AFR) AF: 0.000280 AC: 6 AN: 21406

American (AMR) AF: 0.000478 AC: 4 AN: 8364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12746

East Asian (EAS) AF: 0.0000446 AC: 1 AN: 22432

South Asian (SAS) AF: 0.00 AC: 0 AN: 24194

European-Finnish (FIN) AF: 0.000200 AC: 4 AN: 19962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2744

European-Non Finnish (NFE) AF: 0.00174 AC: 1582 AN: 908284

Other (OTH) AF: 0.00229 AC: 94 AN: 41088

GnomAD4 genome AF: 0.000772 AC: 117 AN: 151584 Hom.: 0 Cov.: 33 AF XY: 0.000635 AC XY: 47 AN XY: 74074

African (AFR) AF: 0.000362 AC: 15 AN: 41470

American (AMR) AF: 0.000328 AC: 5 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10384

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

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 67762

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.000839

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		0.37
PromoterAI		-0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs587780938; hg19: chr6-146056611;