6-145669661-T-C

Variant names:

• chr6-145669661-T-C
• rs702304
• NM_005670.4:c.476+16461A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005670.4(EPM2A):​c.476+16461A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 152,024 control chromosomes in the GnomAD database, including 29,848 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (29848 hom., cov: 32)
• Consequence: EPM2A NM_005670.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06
• Publications: 6 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]

EPM2A Gene-Disease associations (from GenCC):

• Lafora disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia

ENSG00000307801 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4	c.476+16461A>G		intron_variant	Intron 2 of 3	ENST00000367519.9	NP_005661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9	c.476+16461A>G		intron_variant	Intron 2 of 3	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94582 AN: 151906 Hom.: 29816 Cov.: 32

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.636

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.623 AC: 94654 AN: 152024 Hom.: 29848 Cov.: 32 AF XY: 0.619 AC XY: 45994 AN XY: 74308

African (AFR) AF: 0.683 AC: 28318 AN: 41472

American (AMR) AF: 0.710 AC: 10827 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2133 AN: 3466

East Asian (EAS) AF: 0.741 AC: 3827 AN: 5162

South Asian (SAS) AF: 0.485 AC: 2342 AN: 4824

European-Finnish (FIN) AF: 0.508 AC: 5372 AN: 10574

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.585 AC: 39762 AN: 67958

Other (OTH) AF: 0.631 AC: 1334 AN: 2114

Alfa AF: 0.634 Hom.: 5358

Bravo AF: 0.644

Asia WGS AF: 0.587 AC: 2043 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.58
DANN	Benign	0.59
PhyloP100		-2.1
Mutation Taster		=100/0	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: rs702304; hg19: chr6-145990797; COSMIC: COSV62297958; COSMIC: COSV62297958;