chr6-145627563-A-G

Position:

• chr6-145627563-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM2 BP4_Moderate BP6_Very_Strong BS1

The ENST00000638262.1(EPM2A):​c.607T>C​(p.Cys203Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,614,244 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: EPM2A ENST00000638262.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.330

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 -12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07001069).
• BP6: Variant 6-145627563-A-G is Benign according to our data. Variant chr6-145627563-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 137219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-145627563-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000329 (481/1461890) while in subpopulation MID AF= 0.00312 (18/5768). AF 95% confidence interval is 0.00202. There are 1 homozygotes in gnomad4_exome. There are 221 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4	c.849T>C	p.Tyr283=	synonymous_variant	4/4	ENST00000367519.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.849T>C	p.Tyr283=	synonymous_variant	4/4	1	NM_005670.4	P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000312 AC: 78 AN: 250262 Hom.: 0 AF XY: 0.000288 AC XY: 39 AN XY: 135356

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000329 AC: 481 AN: 1461890 Hom.: 1 Cov.: 32 AF XY: 0.000304 AC XY: 221 AN XY: 727246

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000294

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74508

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2014

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Progressive myoclonic epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.38
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.21	T;T
MetaRNN	Benign	0.070	T;T
MutationTaster	Benign	1.0	D
GERP RS		-5.1

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: rs142027344; hg19: chr6-145948699;