chr6-145735422-C-G

Variant names:

• chr6-145735422-C-G
• rs796052433
• NM_005670.4:c.77G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_005670.4(EPM2A):​c.77G>C​(p.Arg26Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000664 in 150,498 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. R26L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• 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]

ENSG00000288551 (HGNC:):

EPM2A-DT (HGNC:48990): (EPM2A divergent transcript)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_005670.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

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.77G>C	p.Arg26Pro	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.77G>C	p.Arg26Pro	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.77G>C	p.Arg26Pro	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.77G>C	p.Arg26Pro	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.77G>C	p.Arg26Pro	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.77G>C	p.Arg26Pro	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150498 Hom.: 0 Cov.: 33

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1104982 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 533242

African (AFR) AF: 0.00 AC: 0 AN: 22558

American (AMR) AF: 0.00 AC: 0 AN: 16720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15648

East Asian (EAS) AF: 0.00 AC: 0 AN: 22316

South Asian (SAS) AF: 0.00 AC: 0 AN: 33840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2964

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 926354

Other (OTH) AF: 0.00 AC: 0 AN: 42810

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150498 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73462

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

American (AMR) AF: 0.00 AC: 0 AN: 15112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9952

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67494

Other (OTH) AF: 0.00 AC: 0 AN: 2068

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.78
Sift	Benign	0.086	T
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.38
MutPred		0.50		Loss of MoRF binding (P = 0.0072)
MVP		0.95
MPC		1.0
ClinPred		0.92	D
GERP RS		3.5
PromoterAI		-0.096	Neutral
gMVP		0.78
Mutation Taster		=16/84	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: rs796052433; hg19: chr6-146056558;