rs767203075

Variant names:

• chr6-145735227-C-G
• rs767203075
• NM_005670.4:c.272G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-145735227-C-G
• chr6-145735227-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_005670.4(EPM2A):​c.272G>C​(p.Arg91Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,385,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R91W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.26
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005670.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793
• PP5: Variant 6-145735227-C-G is Pathogenic according to our data. Variant chr6-145735227-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3776884.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4	c.272G>C	p.Arg91Pro	missense_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.272G>C	p.Arg91Pro	missense_variant	Exon 1 of 4	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1385796 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 685908

African (AFR) AF: 0.00 AC: 0 AN: 29562

American (AMR) AF: 0.00 AC: 0 AN: 36454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23892

East Asian (EAS) AF: 0.00 AC: 0 AN: 34208

South Asian (SAS) AF: 0.00 AC: 0 AN: 78210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5452

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1073170

Other (OTH) AF: 0.00 AC: 0 AN: 56632

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lafora disease Pathogenic:1

Jan 07, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg91Pro variant in EPM2A has been reported in 2 individuals with Lafora disease (PMID: 15009235, 14722920, 16529633), and has been identified in 0.0002% (2/1073170) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 2 affected individuals, 1 was a homozygote, which increases the likelihood that the p.Arg91Pro variant is pathogenic (PMID: 15009235, 16529633). In vitro functional studies provide some evidence that the p.Arg91Pro variant may slightly impact protein function (PMID: 34755096). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg91Pro variant is located in a region of EPM2A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 34755096). The phenotype of an individual homozygous for this variant is highly specific for Lafora disease based on lafora bodies found on biopsy consistent with disease (PMID: 16529633). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Lafora disease. ACMG/AMP Criteria applied: PP3, PM1_supporting, PM2_supporting, PM3_supporting, PS3_supporting, PP4_moderate (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T;T;.;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.7	M;M;M;M
PhyloP100		1.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N;.;D;.
REVEL	Pathogenic	0.72
Sift	Benign	0.14	T;.;D;.
Sift4G	Uncertain	0.018	D;D;.;.
Polyphen		0.99	D;P;P;.
Vest4		0.35
MutPred		0.51		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);
MVP		0.95
MPC		0.98
ClinPred		0.93	D
GERP RS		2.7
PromoterAI		0.083	Neutral
gMVP		0.88
Mutation Taster		=15/85	disease causing

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: rs767203075; hg19: chr6-146056363;