ENST00000639423.1:c.-114+196A>G

Variant names:

• chr6-145735712-T-C
• rs2235481
• ENST00000639423.1:c.-114+196A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000639423.1(EPM2A):​c.-114+196A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.696 in 958,956 control chromosomes in the GnomAD database, including 232,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.73 (40512 hom., cov: 32)
  • Exomes 𝑓: 0.69 (192103 hom.)
• Consequence: EPM2A ENST00000639423.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.711

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]

ENSG00000270638 (HGNC:):

EPM2A-DT (HGNC:48990): (EPM2A divergent transcript)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 6-145735712-T-C is Benign according to our data. Variant chr6-145735712-T-C is described in ClinVar as [Benign]. Clinvar id is 670730.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_001360064.2	c.-114+196A>G		intron_variant	Intron 1 of 3		NP_001346993.1
EPM2A-DT	NR_038246.1	n.52+792T>C		intron_variant	Intron 1 of 2
EPM2A	NR_153398.2	n.116+196A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000639423.1	c.-114+196A>G		intron_variant	Intron 1 of 3	1		ENSP00000492701.1
EPM2A	ENST00000611340.5	c.-114+284A>G		intron_variant	Intron 1 of 3	2		ENSP00000480268.1
EPM2A	ENST00000640980.1	c.-114+196A>G		intron_variant	Intron 1 of 2	3		ENSP00000491191.1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110173 AN: 151956 Hom.: 40470 Cov.: 32

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.739

GnomAD4 exome AF: 0.690 AC: 556707 AN: 806888 Hom.: 192103 Cov.: 11 AF XY: 0.689 AC XY: 261857 AN XY: 379790

Gnomad4 AFR exome AF: 0.820

Gnomad4 AMR exome AF: 0.834

Gnomad4 ASJ exome AF: 0.694

Gnomad4 EAS exome AF: 0.788

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.637

Gnomad4 NFE exome AF: 0.687

Gnomad4 OTH exome AF: 0.702

GnomAD4 genome AF: 0.725 AC: 110263 AN: 152068 Hom.: 40512 Cov.: 32 AF XY: 0.722 AC XY: 53652 AN XY: 74332

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.802

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.788

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.579

Gnomad4 NFE AF: 0.681

Gnomad4 OTH AF: 0.733

Alfa AF: 0.689 Hom.: 53743

Bravo AF: 0.748

Asia WGS AF: 0.678 AC: 2357 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.7
DANN	Benign	0.57

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: rs2235481; hg19: chr6-146056848;