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. The variant received -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
• Publications: 19 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]

ENSG00000270638 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000639423.1. 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_001360064.2		c.-114+196A>G		intron	N/A	NP_001346993.1	O95278-8
	EPM2A-DT	NR_038246.1		n.52+792T>C		intron	N/A
	EPM2A	NR_153398.2		n.116+196A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000639423.1	TSL:1	c.-114+196A>G		intron	N/A	ENSP00000492701.1	O95278-8
	EPM2A	ENST00000611340.5	TSL:2	c.-114+284A>G		intron	N/A	ENSP00000480268.1	O95278-8
	EPM2A	ENST00000640980.1	TSL:3	c.-114+196A>G		intron	N/A	ENSP00000491191.1	A0A1W2PPJ6

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

African (AFR) AF: 0.820 AC: 12637 AN: 15418

American (AMR) AF: 0.834 AC: 2618 AN: 3140

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 4861 AN: 7002

East Asian (EAS) AF: 0.788 AC: 7592 AN: 9634

South Asian (SAS) AF: 0.594 AC: 8962 AN: 15078

European-Finnish (FIN) AF: 0.637 AC: 5029 AN: 7900

Middle Eastern (MID) AF: 0.724 AC: 1328 AN: 1834

European-Non Finnish (NFE) AF: 0.687 AC: 493483 AN: 718100

Other (OTH) AF: 0.702 AC: 20197 AN: 28782

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

African (AFR) AF: 0.815 AC: 33846 AN: 41522

American (AMR) AF: 0.802 AC: 12270 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2395 AN: 3470

East Asian (EAS) AF: 0.788 AC: 4032 AN: 5116

South Asian (SAS) AF: 0.598 AC: 2883 AN: 4820

European-Finnish (FIN) AF: 0.579 AC: 6112 AN: 10564

Middle Eastern (MID) AF: 0.688 AC: 201 AN: 292

European-Non Finnish (NFE) AF: 0.681 AC: 46254 AN: 67966

Other (OTH) AF: 0.733 AC: 1548 AN: 2112

Alfa AF: 0.696 Hom.: 88487

Bravo AF: 0.748

Asia WGS AF: 0.678 AC: 2357 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.7
DANN	Benign	0.57
PhyloP100		-0.71
PromoterAI		-0.039	Neutral
Mutation Taster		=300/0	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: rs2235481; hg19: chr6-146056848;