6-145735336-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005670.4(EPM2A):c.163C>G(p.Gln55Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000217 in 1,383,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign 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. Q55K) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.35

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-DT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain CBM20 (size 123) in uniprot entity EPM2A_HUMAN there are 16 pathogenic changes around while only 4 benign (80%) in NM_005670.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25504282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2A	NM_005670.4	c.163C>G	p.Gln55Glu	missense_variant	1/4	ENST00000367519.9
EPM2A-DT	NR_038246.1	n.52+416G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2A	ENST00000367519.9	c.163C>G	p.Gln55Glu	missense_variant	1/4	1	NM_005670.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000162 AC: 2 AN: 1232942 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 607692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000201

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73278

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	16
Dann	Benign	0.66
DEOGEN2	Benign	0.32	T;.;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T;T;.;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.1	L;L;L;L
MutationTaster	Benign	0.78	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.21	N;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.82	T;.;.;.
Sift4G	Benign	0.18	T;T;.;.
Polyphen		0.0010	B;B;B;.
Vest4		0.13
MutPred		0.38		Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);Gain of disorder (P = 0.0619);
MVP		0.95
MPC		0.26
ClinPred		0.17	T
GERP RS		3.5
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs187930476; hg19: chr6-146056472;