chr6-145502506-G-A

Variant names:

• chr6-145502506-G-A
• rs370653
• ENST00000638717.1:c.553+16C>T

Variant summary

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

The ENST00000450221.6(EPM2A):​c.394+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 468,968 control chromosomes in the GnomAD database, including 52,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (15466 hom., cov: 32)
  • Exomes 𝑓: 0.48 (37189 hom.)
• Consequence: EPM2A ENST00000450221.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.753

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-145502506-G-A is Benign according to our data. Variant chr6-145502506-G-A is described in ClinVar as [Benign]. Clinvar id is 3255263.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-145502506-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	XM_024446550.2	c.772+16C>T		intron_variant	Intron 4 of 4		XP_024302318.1
EPM2A	XM_011536113.3	c.772+16C>T		intron_variant	Intron 4 of 4		XP_011534415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000638717.1	c.553+16C>T		intron_variant	Intron 4 of 4	5		ENSP00000491330.1
EPM2A	ENST00000450221.6	c.394+16C>T		intron_variant	Intron 3 of 3	3		ENSP00000414900.2

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68434 AN: 151962 Hom.: 15443 Cov.: 32

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.441

GnomAD3 exomes AF: 0.469 AC: 68494 AN: 145920 Hom.: 16460 AF XY: 0.479 AC XY: 37713 AN XY: 78726

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.401

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.413

Gnomad SAS exome AF: 0.584

Gnomad FIN exome AF: 0.512

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.462

GnomAD4 exome AF: 0.479 AC: 151869 AN: 316888 Hom.: 37189 Cov.: 0 AF XY: 0.490 AC XY: 87730 AN XY: 179190

Gnomad4 AFR exome AF: 0.420

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.450

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.577

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.460

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.450 AC: 68501 AN: 152080 Hom.: 15466 Cov.: 32 AF XY: 0.456 AC XY: 33884 AN XY: 74320

Gnomad4 AFR AF: 0.413

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.427

Gnomad4 SAS AF: 0.584

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.463

Gnomad4 OTH AF: 0.447

Alfa AF: 0.444 Hom.: 2738

Bravo AF: 0.438

Asia WGS AF: 0.533 AC: 1851 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 55. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.1
DANN	Benign	0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs370653; hg19: chr6-145823642;