rs753397854

Variant names:

• chr6-145735351-C-A
• rs753397854
• NM_005670.4:c.148G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-145735351-C-A
• chr6-145735351-C-T
• chr6-145735351-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001360071.2(EPM2A):​c.-522G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,057,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: EPM2A NM_001360071.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.706
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3528105).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360071.2. 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.148G>T	p.Gly50Trp	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360071.2		c.-522G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001347000.1	O95278-8
	EPM2A	NM_001368131.1		c.-220G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001355060.1	O95278-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.148G>T	p.Gly50Trp	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.148G>T	p.Gly50Trp	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.148G>T	p.Gly50Trp	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 41974 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000284 AC: 3 AN: 1057814 Hom.: 0 Cov.: 34 AF XY: 0.00000387 AC XY: 2 AN XY: 516144

African (AFR) AF: 0.0000992 AC: 2 AN: 20162

American (AMR) AF: 0.00 AC: 0 AN: 12196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12534

East Asian (EAS) AF: 0.00 AC: 0 AN: 14704

South Asian (SAS) AF: 0.00 AC: 0 AN: 47730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2586

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 893198

Other (OTH) AF: 0.0000260 AC: 1 AN: 38490

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.4	L
PhyloP100		0.71
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.21
MutPred		0.35		Loss of disorder (P = 0.011)
MVP		0.96
MPC		0.71
ClinPred		0.68	D
GERP RS		2.5
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
gMVP		0.47
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753397854; hg19: chr6-146056487;