6-145625446-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005670.4(EPM2A):c.*1970T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 489,442 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 33)
  • Exomes 𝑓: 0.012 (39 hom.)
• Consequence: EPM2A NM_005670.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.562

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=-0.9).
• BP6: Variant 6-145625446-A-G is Benign according to our data. Variant chr6-145625446-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1197768.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-145625446-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0108 (1649/152344) while in subpopulation AMR AF= 0.0175 (268/15312). AF 95% confidence interval is 0.0158. There are 13 homozygotes in gnomad4. There are 766 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4	c.*1970T>C		3_prime_UTR_variant	4/4	ENST00000367519.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.*1970T>C		3_prime_UTR_variant	4/4	1	NM_005670.4	P1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1641 AN: 152226 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0124 AC: 4183 AN: 337098 Hom.: 39 Cov.: 0 AF XY: 0.0125 AC XY: 2215 AN XY: 177376

Gnomad4 AFR exome AF: 0.00887

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.00320

Gnomad4 EAS exome AF: 0.00152

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.00514

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0108 AC: 1649 AN: 152344 Hom.: 13 Cov.: 33 AF XY: 0.0103 AC XY: 766 AN XY: 74500

Gnomad4 AFR AF: 0.00712

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0118 Hom.: 2

Bravo AF: 0.0120

Asia WGS AF: 0.0140 AC: 49 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.13
Dann	Benign	0.54

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: rs117055625; hg19: chr6-145946582;