6-145735513-G-T

Variant names:

• chr6-145735513-G-T
• rs7771112
• NM_005670.4:c.-15C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005670.4(EPM2A):​c.-15C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,183,262 control chromosomes in the GnomAD database, including 1,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (1131 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (634 hom.)
• Consequence: EPM2A NM_005670.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.578
• Publications: 1 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]

ENSG00000288551 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-145735513-G-T is Benign according to our data. Variant chr6-145735513-G-T is described in ClinVar as Benign. ClinVar VariationId is 137221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4	c.-15C>A		5_prime_UTR_variant	Exon 1 of 4	ENST00000367519.9	NP_005661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9	c.-15C>A		5_prime_UTR_variant	Exon 1 of 4	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes AF: 0.0666 AC: 10094 AN: 151662 Hom.: 1127 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.0613

GnomAD2 exomes AF: 0.00 AC: 0 AN: 76 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00607 AC: 6259 AN: 1031492 Hom.: 634 Cov.: 35 AF XY: 0.00545 AC XY: 2653 AN XY: 487176

African (AFR) AF: 0.238 AC: 4948 AN: 20800

American (AMR) AF: 0.0250 AC: 167 AN: 6676

Ashkenazi Jewish (ASJ) AF: 0.00143 AC: 17 AN: 11896

East Asian (EAS) AF: 0.00 AC: 0 AN: 21678

South Asian (SAS) AF: 0.000250 AC: 5 AN: 20016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18950

Middle Eastern (MID) AF: 0.0122 AC: 32 AN: 2616

European-Non Finnish (NFE) AF: 0.000530 AC: 471 AN: 889098

Other (OTH) AF: 0.0156 AC: 619 AN: 39762

GnomAD4 genome AF: 0.0666 AC: 10105 AN: 151770 Hom.: 1131 Cov.: 33 AF XY: 0.0646 AC XY: 4791 AN XY: 74168

African (AFR) AF: 0.225 AC: 9328 AN: 41472

American (AMR) AF: 0.0363 AC: 555 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 67796

Other (OTH) AF: 0.0607 AC: 128 AN: 2110

Alfa AF: 0.0474 Hom.: 94

Bravo AF: 0.0779

Asia WGS AF: 0.00812 AC: 28 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 06, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2012

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 03, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.1
DANN	Benign	0.94
PhyloP100		0.58
PromoterAI		0.0086	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: rs7771112; hg19: chr6-146056649;