NM_000085.5:c.80G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000085.5(CLCNKB):c.80G>T(p.Arg27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 1,600,392 control chromosomes in the GnomAD database, including 316,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R27C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.55 ( 24645 hom., cov: 32)

Exomes 𝑓: 0.63 ( 292311 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.00800

Publications

31 publications found

Variant links:

Genes affected

CLCNKB (HGNC:2027): (chloride voltage-gated channel Kb) The protein encoded by this gene is a member of the family of voltage-gated chloride channels. Chloride channels have several functions, including the regulation of cell volume, membrane potential stabilization, signal transduction and transepithelial transport. This gene is expressed predominantly in the kidney and may be important for renal salt reabsorption. Mutations in this gene are associated with autosomal recessive Bartter syndrome type 3 (BS3). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

CLCNKB Gene-Disease associations (from GenCC):

Bartter disease type 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
Bartter disease type 4B
Inheritance: AR Classification: STRONG Submitted by: G2P
Bartter syndrome type 4
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Gitelman syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLCNKB 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=2.8500958E-6).

BP6

Variant 1-16044572-G-T is Benign according to our data. Variant chr1-16044572-G-T is described in ClinVar as Benign. ClinVar VariationId is 447107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.80G>T	p.Arg27Leu	missense_variant	Exon 2 of 20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.80G>T	p.Arg27Leu	missense_variant	Exon 2 of 20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.548

AC:

83175

AN:

151712

Hom.:

24634

Cov.:

show subpopulations

Gnomad AFR

AF:

0.301

Gnomad AMI

AF:

0.758

Gnomad AMR

AF:

0.667

Gnomad ASJ

AF:

0.672

Gnomad EAS

AF:

0.664

Gnomad SAS

AF:

0.682

Gnomad FIN

AF:

0.558

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.641

Gnomad OTH

AF:

0.591

GnomAD2 exomes

AF:

0.627

AC:

142132

AN:

226810

AF XY:

0.632

show subpopulations

Gnomad AFR exome

AF:

0.288

Gnomad AMR exome

AF:

0.729

Gnomad ASJ exome

AF:

0.683

Gnomad EAS exome

AF:

0.633

Gnomad FIN exome

AF:

0.555

Gnomad NFE exome

AF:

0.633

Gnomad OTH exome

AF:

0.633

GnomAD4 exome

AF:

0.632

AC:

915382

AN:

1448564

Hom.:

292311

Cov.:

AF XY:

0.635

AC XY:

456403

AN XY:

719082

show subpopulations

African (AFR)

AF:

0.282

AC:

9431

AN:

33404

American (AMR)

AF:

0.718

AC:

30413

AN:

42376

Ashkenazi Jewish (ASJ)

AF:

0.679

AC:

17485

AN:

25752

East Asian (EAS)

AF:

0.690

AC:

27069

AN:

39240

South Asian (SAS)

AF:

0.685

AC:

57060

AN:

83312

European-Finnish (FIN)

AF:

0.558

AC:

29353

AN:

52566

Middle Eastern (MID)

AF:

0.685

AC:

3937

AN:

5748

European-Non Finnish (NFE)

AF:

0.636

AC:

703283

AN:

1106244

Other (OTH)

AF:

0.623

AC:

37351

AN:

59922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16443

32885

49328

65770

82213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18622

37244

55866

74488

93110

<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:

0.548

AC:

83204

AN:

151828

Hom.:

24645

Cov.:

AF XY:

0.549

AC XY:

40765

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.300

AC:

12425

AN:

41364

American (AMR)

AF:

0.667

AC:

10186

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.672

AC:

2329

AN:

3466

East Asian (EAS)

AF:

0.664

AC:

3423

AN:

5154

South Asian (SAS)

AF:

0.683

AC:

3278

AN:

4802

European-Finnish (FIN)

AF:

0.558

AC:

5899

AN:

10564

Middle Eastern (MID)

AF:

0.660

AC:

194

AN:

294

European-Non Finnish (NFE)

AF:

0.641

AC:

43531

AN:

67896

Other (OTH)

AF:

0.593

AC:

1251

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1731

3463

5194

6926

8657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.611

Hom.:

28124

Bravo

AF:

0.545

TwinsUK

AF:

0.628

AC:

2328

ALSPAC

AF:

0.615

AC:

2372

ESP6500AA

AF:

0.300

AC:

1322

ESP6500EA

AF:

0.642

AC:

5523

ExAC

AF:

0.601

AC:

72401

Asia WGS

AF:

0.613

AC:

2132

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg27Leu in exon 2 of CLCNKB: This variant is not expected to have clinical si gnificance because it has been identified in 75.85% (6139/8094) of Latino chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2015352). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bartter disease type 3

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bartter disease type 4B

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

.;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.079

T;T

MetaRNN

Benign

0.0000029

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.7

.;M

PhyloP100

0.0080

PROVEAN

Uncertain

-3.0

.;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.025

.;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.47

.;P

Vest4

0.093

MPC

0.046

ClinPred

0.028

GERP RS

3.2

Varity_R

0.14

gMVP

0.58

Mutation Taster

=92/8

polymorphism (auto)

(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