rs763719276

Variant names:

• chr6-145735342-C-T
• rs763719276
• NM_005670.4:c.157G>A
• EPM2A p.Ala53Thr

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_005670.4(EPM2A):​c.157G>A​(p.Ala53Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000888 in 1,362,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 2.63
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034620583).
• BP6: Variant 6-145735342-C-T is Benign according to our data. Variant chr6-145735342-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205430.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000891 (108/1212682) while in subpopulation MID AF = 0.002 (7/3496). AF 95% confidence interval is 0.000939. There are 0 homozygotes in GnomAdExome4. There are 55 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

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.157G>A	p.Ala53Thr	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.157G>A	p.Ala53Thr	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.157G>A	p.Ala53Thr	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.157G>A	p.Ala53Thr	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.157G>A	p.Ala53Thr	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.157G>A	p.Ala53Thr	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.0000866 AC: 13 AN: 150056 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000214 AC: 15 AN: 69968 AF XY: 0.000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000507

GnomAD4 exome AF: 0.0000891 AC: 108 AN: 1212682 Hom.: 0 Cov.: 35 AF XY: 0.0000923 AC XY: 55 AN XY: 595930

African (AFR) AF: 0.00 AC: 0 AN: 24520

American (AMR) AF: 0.000186 AC: 4 AN: 21488

Ashkenazi Jewish (ASJ) AF: 0.000827 AC: 16 AN: 19336

East Asian (EAS) AF: 0.00 AC: 0 AN: 24044

South Asian (SAS) AF: 0.000155 AC: 9 AN: 58078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29468

Middle Eastern (MID) AF: 0.00200 AC: 7 AN: 3496

European-Non Finnish (NFE) AF: 0.0000599 AC: 59 AN: 984296

Other (OTH) AF: 0.000271 AC: 13 AN: 47956

GnomAD4 genome AF: 0.0000866 AC: 13 AN: 150056 Hom.: 0 Cov.: 33 AF XY: 0.0000546 AC XY: 4 AN XY: 73204

African (AFR) AF: 0.00 AC: 0 AN: 41222

American (AMR) AF: 0.0000663 AC: 1 AN: 15084

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 5 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9810

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

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67264

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000982

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.6
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.33	N
REVEL	Benign	0.14
Sift	Benign	0.60	T
Sift4G	Benign	0.15	T
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.26
Mutation Taster		=71/29	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs763719276;

hg19: chr6-146056478;