NM_004366.6:c.597dupG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_004366.6(CLCN2):c.597dupG(p.Met200AspfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CLCN2
NM_004366.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1U:1

Conservation

PhyloP100: -0.452

Publications

6 publications found

Variant links:

Genes affected

CLCN2 (HGNC:2020): (chloride voltage-gated channel 2) This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

CLCN2 Gene-Disease associations (from GenCC):

leukoencephalopathy with mild cerebellar ataxia and white matter edema
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
epilepsy, idiopathic generalized, susceptibility to, 11
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
familial hyperaldosteronism type II
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CLCN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-184357979-T-TC is Pathogenic according to our data. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184357979-T-TC is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 9035.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN2	NM_004366.6 link	c.597dupG	p.Met200AspfsTer32	frameshift_variant	Exon 5 of 24	ENST00000265593.9	NP_004357.3	P51788-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9 link	c.597dupG	p.Met200AspfsTer32	frameshift_variant	Exon 5 of 24	1	NM_004366.6	ENSP00000265593.4		P51788-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251350

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461696

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Pathogenic:1

Sep 09, 2015

GeneReviews

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

EPILEPSY, JUVENILE MYOCLONIC, SUSCEPTIBILITY TO, 8

Uncertain:1

Sep 01, 2009

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.45

Mutation Taster

=6/194

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over