rs547147183

chr6-145735370-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The NM_005670.4(EPM2A):c.129C>G(p.Ala43=) 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

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]

EPM2A-DT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 137223.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=2}.
• 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4	c.129C>G	p.Ala43=	synonymous_variant	1/4	ENST00000367519.9
EPM2A-DT	NR_038246.1	n.52+450G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.129C>G	p.Ala43=	synonymous_variant	1/4	1	NM_005670.4	P1

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

GnomAD3 exomes AF: 0.000176 AC: 2 AN: 11338 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 7226

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 SAS 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

Gnomad4 AFR exome AF: 0.00358

Gnomad4 AMR exome AF: 0.000343

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000296

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000182

Gnomad4 OTH exome AF: 0.000375

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

Gnomad4 AFR AF: 0.00446

Gnomad4 AMR AF: 0.000399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000896

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.00126

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 15, 2018

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 24, 2013

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Progressive myoclonic epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	5.3
Dann	Benign	0.32
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

Publications

LitVar

Other links and lift over

dbSNP: rs547147183; hg19: chr6-146056506;