NM_004366.6:c.143C>G

Variant names:

Variant summary

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

The NM_004366.6(CLCN2):c.143C>G(p.Pro48Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,613,656 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 11 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 8 hom. )

Consequence

CLCN2
NM_004366.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.678

Publications

4 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049925745).

BP6

Variant 3-184359052-G-C is Benign according to our data. Variant chr3-184359052-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 217768.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 = 0.00567 (864/152310) while in subpopulation AFR AF = 0.0199 (828/41576). AF 95% confidence interval is 0.0188. There are 11 homozygotes in GnomAd4. There are 433 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN2	NM_004366.6 link	c.143C>G	p.Pro48Arg	missense_variant	Exon 2 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.143C>G	p.Pro48Arg	missense_variant	Exon 2 of 24	1	NM_004366.6	ENSP00000265593.4		P51788-1

Frequencies

GnomAD3 genomes

AF:

0.00564

AC:

858

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

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:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00153

AC:

385

AN:

251080

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.0213

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000580

AC:

847

AN:

1461346

Hom.:

Cov.:

AF XY:

0.000459

AC XY:

334

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.0209

AC:

700

AN:

33480

American (AMR)

AF:

0.000917

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52878

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1112008

Other (OTH)

AF:

0.00139

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

118

176

235

294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00567

AC:

864

AN:

152310

Hom.:

Cov.:

AF XY:

0.00581

AC XY:

433

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0199

AC:

828

AN:

41576

American (AMR)

AF:

0.00189

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.00621

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00177

AC:

215

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Leukoencephalopathy with mild cerebellar ataxia and white matter edema

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.077

T;.;.;.;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.76

T;T;T;T;T

MetaRNN

Benign

0.0050

T;T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.81

L;L;L;L;.

PhyloP100

0.68

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.87

N;N;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.49

T;T;T;T;.

Sift4G

Benign

0.59

T;T;T;T;.

Polyphen

0.022

B;B;.;.;.

Vest4

0.29

MVP

0.81

MPC

0.30

ClinPred

0.0047

GERP RS

2.5

PromoterAI

0.091

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.22

Mutation Taster

=299/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over