rs146321088

Variant names:

• chr6-145627690-C-A
• rs146321088
• NM_005670.4:c.722G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-145627690-C-A
• chr6-145627690-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005670.4(EPM2A):​c.722G>T​(p.Arg241Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R241Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2A	NM_005670.4	c.722G>T	p.Arg241Leu	missense_variant	Exon 4 of 4	ENST00000367519.9	NP_005661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2A	ENST00000367519.9	c.722G>T	p.Arg241Leu	missense_variant	Exon 4 of 4	1	NM_005670.4	ENSP00000356489.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461654 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.;.;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;.;.;.;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.1	L;.;L;.;L;.;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.0	N;.;.;.;.;.;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.022	D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;.;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;D;.;.;.
Vest4		0.84
MutPred		0.65		Gain of loop (P = 0.0195);.;Gain of loop (P = 0.0195);.;Gain of loop (P = 0.0195);.;.;.;
MVP		0.92
MPC		0.67
ClinPred		0.87	D
GERP RS		5.7
gMVP		0.81
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: rs146321088; hg19: chr6-145948826;