rs374338349

Variant names:

• chr6-145735363-C-G
• rs374338349
• NM_005670.4:c.136G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-145735363-C-G
• chr6-145735363-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005670.4(EPM2A):​c.136G>C​(p.Ala46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 788,066 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (75 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.0750
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021043122).
• BP6: Variant 6-145735363-C-G is Benign according to our data. Variant chr6-145735363-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

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.136G>C	p.Ala46Pro	missense	Exon 1 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001018041.2		c.136G>C	p.Ala46Pro	missense	Exon 1 of 5	NP_001018051.1	O95278-2
	EPM2A	NM_001368130.1		c.136G>C	p.Ala46Pro	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.136G>C	p.Ala46Pro	missense	Exon 1 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000435470.2	TSL:1	c.136G>C	p.Ala46Pro	missense	Exon 1 of 5	ENSP00000405913.2	O95278-2
	EPM2A	ENST00000638262.1	TSL:1	c.136G>C	p.Ala46Pro	missense	Exon 1 of 3	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 602 AN: 139548 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.000505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000633

Gnomad ASJ AF: 0.00215

Gnomad EAS AF: 0.0878

Gnomad SAS AF: 0.00919

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000473

Gnomad OTH AF: 0.00507

GnomAD2 exomes AF: 0.0103 AC: 117 AN: 11398 AF XY: 0.0108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.000987

Gnomad OTH exome AF: 0.00773

GnomAD4 exome AF: 0.00373 AC: 2421 AN: 648384 Hom.: 75 Cov.: 24 AF XY: 0.00375 AC XY: 1196 AN XY: 318756

African (AFR) AF: 0.000246 AC: 3 AN: 12192

American (AMR) AF: 0.00 AC: 0 AN: 3988

Ashkenazi Jewish (ASJ) AF: 0.00568 AC: 35 AN: 6166

East Asian (EAS) AF: 0.156 AC: 1349 AN: 8634

South Asian (SAS) AF: 0.00838 AC: 227 AN: 27090

European-Finnish (FIN) AF: 0.0432 AC: 365 AN: 8456

Middle Eastern (MID) AF: 0.00138 AC: 2 AN: 1454

European-Non Finnish (NFE) AF: 0.000393 AC: 219 AN: 556928

Other (OTH) AF: 0.00941 AC: 221 AN: 23476

GnomAD4 genome AF: 0.00436 AC: 609 AN: 139682 Hom.: 17 Cov.: 32 AF XY: 0.00523 AC XY: 354 AN XY: 67748

African (AFR) AF: 0.000504 AC: 20 AN: 39716

American (AMR) AF: 0.000632 AC: 9 AN: 14246

Ashkenazi Jewish (ASJ) AF: 0.00215 AC: 7 AN: 3256

East Asian (EAS) AF: 0.0881 AC: 357 AN: 4050

South Asian (SAS) AF: 0.00965 AC: 37 AN: 3834

European-Finnish (FIN) AF: 0.0168 AC: 135 AN: 8014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000473 AC: 30 AN: 63434

Other (OTH) AF: 0.00703 AC: 14 AN: 1992

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.00359

ExAC AF: 0.00683 AC: 61

Asia WGS AF: 0.0430 AC: 138 AN: 3234

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Lafora disease (2)
-	-	1	not provided (1)
-	-	1	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.075
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.25
Sift	Benign	0.36	T
Sift4G	Benign	0.28	T
Polyphen		0.96	D
Vest4		0.15
MPC		0.31
ClinPred		0.048	T
GERP RS		2.4
PromoterAI		-0.064	Neutral
gMVP		0.29
Mutation Taster		=96/4	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: rs374338349; hg19: chr6-146056499;