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 Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV005907572: "In vitro functional studies provide some evidence that the p.Arg91Pro variant may slightly impact protein function." PMID:34755096". 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: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005907572: "In vitro functional studies provide some evidence that the p.Arg91Pro variant may slightly impact protein function." PMID:34755096
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005670.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	NM_005670.4	MANE Select	c.272G>C	p.Arg91Pro	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.272G>C	p.Arg91Pro	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.272G>C	p.Arg91Pro	missense	Exon 1 of 3	NP_001355059.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.272G>C	p.Arg91Pro	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.272G>C	p.Arg91Pro	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.272G>C	p.Arg91Pro	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Lafora disease (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.72
Sift	Benign	0.14	T
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.35
MutPred		0.51		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;