rs531330673

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-145735328-C-A
• chr6-145735328-C-G
• chr6-145735328-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005670.4(EPM2A):​c.171G>T​(p.Pro57Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000378 in 1,304,038 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P57P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: EPM2A NM_005670.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 6-145735328-C-A is Benign according to our data. Variant chr6-145735328-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.497 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000447 (66/147812) while in subpopulation EAS AF = 0.0127 (62/4890). AF 95% confidence interval is 0.0102. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	NM_005670.4	MANE Select	c.171G>T	p.Pro57Pro	synonymous	Exon 1 of 4	NP_005661.1
	EPM2A	NM_001360071.2		c.-499G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001347000.1
	EPM2A	NM_001368131.1		c.-197G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001355060.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 66 AN: 147686 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000671

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0126

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.000491

GnomAD2 exomes AF: 0.000689 AC: 57 AN: 82722 AF XY: 0.000615

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000688

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000369 AC: 427 AN: 1156226 Hom.: 4 Cov.: 30 AF XY: 0.000357 AC XY: 203 AN XY: 568576

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

American (AMR) AF: 0.0000880 AC: 2 AN: 22716

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

East Asian (EAS) AF: 0.0253 AC: 396 AN: 15674

South Asian (SAS) AF: 0.0000572 AC: 4 AN: 69882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23608

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

European-Non Finnish (NFE) AF: 0.0000160 AC: 15 AN: 938586

Other (OTH) AF: 0.000230 AC: 10 AN: 43422

GnomAD4 genome AF: 0.000447 AC: 66 AN: 147812 Hom.: 0 Cov.: 32 AF XY: 0.000582 AC XY: 42 AN XY: 72134

African (AFR) AF: 0.0000244 AC: 1 AN: 40988

American (AMR) AF: 0.0000670 AC: 1 AN: 14918

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

East Asian (EAS) AF: 0.0127 AC: 62 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: 0.000486 AC: 1 AN: 2058

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.000574

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.0
DANN	Benign	0.78
PhyloP100		-0.50
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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; COSMIC: COSV62295932; COSMIC: COSV62295932;