dbSNP rs145030227: EPM2A:c.719-4G>A (chr6-145627697-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005670.4(EPM2A):c.719-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,613,724 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

EPM2A
NM_005670.4 splice_region, intron

Scores

Splicing: ADA: 0.00005769

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.136

Publications

2 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Lafora disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

EPM2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 6-145627697-C-T is Benign according to our data. Variant chr6-145627697-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00165 (251/152332) while in subpopulation AFR AF = 0.00585 (243/41566). AF 95% confidence interval is 0.00524. There are 2 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EPM2A	NM_005670.4	MANE Select	c.719-4G>A	splice_region intron	N/A	NP_005661.1	O95278-1
EPM2A	NM_001018041.2		c.719-4G>A	splice_region intron	N/A	NP_001018051.1	O95278-2
EPM2A	NM_001360057.2		c.477-4G>A	splice_region intron	N/A	NP_001346986.1	O95278-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.719-4G>A	splice_region intron	N/A	ENSP00000356489.3	O95278-1
EPM2A	ENST00000435470.2	TSL:1	c.719-4G>A	splice_region intron	N/A	ENSP00000405913.2	O95278-2
EPM2A	ENST00000638262.1	TSL:1	c.477-4G>A	splice_region intron	N/A	ENSP00000492876.1	O95278-5

Frequencies

GnomAD3 genomes

AF:

0.00165

AC:

251

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00586

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000478

GnomAD2 exomes

AF:

0.000412

AC:

102

AN:

247462

AF XY:

0.000283

show subpopulations

Gnomad AFR exome

AF:

0.00622

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000190

AC:

278

AN:

1461392

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00687

AC:

230

AN:

33472

American (AMR)

AF:

0.0000895

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.000883

AC:

AN:

5662

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111942

Other (OTH)

AF:

0.000249

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00165

AC:

251

AN:

152332

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

129

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00585

AC:

243

AN:

41566

American (AMR)

AF:

0.000458

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.00186

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Inborn genetic diseases (1)

Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.7

(source)

DANN

Benign

0.72

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000058

dbscSNV1_RF

Benign

0.0060

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over