chr6-145735329-G-A

Variant names:

• chr6-145735329-G-A
• rs1229724993
• NM_005670.4:c.170C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001360071.2(EPM2A):​c.-500C>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 0.00000768 in 1,432,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000078 (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: 1.49
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.170C>T	p.Pro57Leu	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360071.2		c.-500C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001347000.1	O95278-8
	EPM2A	NM_001368131.1		c.-198C>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.170C>T	p.Pro57Leu	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.170C>T	p.Pro57Leu	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.170C>T	p.Pro57Leu	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150542 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000124 AC: 1 AN: 80852 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: 0.0000351

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000780 AC: 10 AN: 1281614 Hom.: 0 Cov.: 30 AF XY: 0.00000950 AC XY: 6 AN XY: 631838

African (AFR) AF: 0.0000781 AC: 2 AN: 25618

American (AMR) AF: 0.0000386 AC: 1 AN: 25910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21396

East Asian (EAS) AF: 0.00 AC: 0 AN: 25742

South Asian (SAS) AF: 0.00 AC: 0 AN: 70348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4178

European-Non Finnish (NFE) AF: 0.00000587 AC: 6 AN: 1021678

Other (OTH) AF: 0.0000193 AC: 1 AN: 51770

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150542 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73482

African (AFR) AF: 0.00 AC: 0 AN: 41236

American (AMR) AF: 0.0000662 AC: 1 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67498

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.31
MutPred		0.49		Gain of helix (P = 0.0093)
MVP		0.94
MPC		0.88
ClinPred		0.98	D
GERP RS		3.5
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.62
Mutation Taster		=56/44	polymorphism

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: rs1229724993; hg19: chr6-146056465;