rs104893955

Variant names:

• chr6-145735405-A-C
• rs104893955
• NM_005670.4:c.94T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-145735405-A-C
• chr6-145735405-A-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_005670.4(EPM2A):​c.94T>G​(p.Trp32Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,243,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W32R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 9.1e-7 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.62
• Publications: 15 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_005670.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 6-145735405-A-C is Pathogenic according to our data. Variant chr6-145735405-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.94T>G	p.Trp32Gly	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.94T>G	p.Trp32Gly	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.94T>G	p.Trp32Gly	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.94T>G	p.Trp32Gly	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.94T>G	p.Trp32Gly	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.94T>G	p.Trp32Gly	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149622 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000244

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093504 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 527836

African (AFR) AF: 0.00 AC: 0 AN: 21874

American (AMR) AF: 0.00 AC: 0 AN: 13836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14672

East Asian (EAS) AF: 0.00 AC: 0 AN: 21898

South Asian (SAS) AF: 0.00 AC: 0 AN: 31560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2902

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 923414

Other (OTH) AF: 0.00 AC: 0 AN: 42142

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149730 Hom.: 0 Cov.: 33 AF XY: 0.0000137 AC XY: 1 AN XY: 73070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000243 AC: 1 AN: 41158

American (AMR) AF: 0.00 AC: 0 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67148

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Lafora disease (1)
1	-	-	Myoclonic epilepsy of Lafora 1 (1)
1	-	-	not provided (1)
1	-	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		1.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.70		Gain of relative solvent accessibility (P = 0.005)
MVP		0.96
MPC		1.2
ClinPred		0.99	D
GERP RS		2.4
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.85
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs104893955; hg19: chr6-146056541;