1-16053748-A-G

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.1732A>G(p.Lys578Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,610,920 control chromosomes in the GnomAD database, including 363,773 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 37137 hom., cov: 32)

Exomes 𝑓: 0.67 ( 326636 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.01

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=5.6256567E-6).

BP6

Variant 1-16053748-A-G is Benign according to our data. Variant chr1-16053748-A-G is described in ClinVar as Benign. ClinVar VariationId is 447096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.1732A>G	p.Lys578Glu	missense_variant	Exon 16 of 20	ENST00000375679.9	NP_000076.2
CLCNKB	NM_001165945.2 link	c.1225A>G	p.Lys409Glu	missense_variant	Exon 9 of 13		NP_001159417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.1732A>G	p.Lys578Glu	missense_variant	Exon 16 of 20	1	NM_000085.5	ENSP00000364831.5

Frequencies

GnomAD3 genomes

AF:

0.695

AC:

105369

AN:

151652

Hom.:

37116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.799

Gnomad AMI

AF:

0.453

Gnomad AMR

AF:

0.577

Gnomad ASJ

AF:

0.581

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.739

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.661

Gnomad OTH

AF:

0.668

GnomAD2 exomes

AF:

0.653

AC:

163268

AN:

250048

AF XY:

0.650

show subpopulations

Gnomad AFR exome

AF:

0.798

Gnomad AMR exome

AF:

0.518

Gnomad ASJ exome

AF:

0.582

Gnomad EAS exome

AF:

0.795

Gnomad FIN exome

AF:

0.739

Gnomad NFE exome

AF:

0.659

Gnomad OTH exome

AF:

0.655

GnomAD4 exome

AF:

0.667

AC:

973531

AN:

1459150

Hom.:

326636

Cov.:

AF XY:

0.664

AC XY:

482151

AN XY:

725916

show subpopulations

African (AFR)

AF:

0.807

AC:

27025

AN:

33468

American (AMR)

AF:

0.524

AC:

23423

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

15366

AN:

26100

East Asian (EAS)

AF:

0.811

AC:

32172

AN:

39690

South Asian (SAS)

AF:

0.583

AC:

50209

AN:

86170

European-Finnish (FIN)

AF:

0.737

AC:

39134

AN:

53124

Middle Eastern (MID)

AF:

0.590

AC:

3399

AN:

5762

European-Non Finnish (NFE)

AF:

0.669

AC:

742546

AN:

1109832

Other (OTH)

AF:

0.667

AC:

40257

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

18415

36830

55246

73661

92076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19296

38592

57888

77184

96480

<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:

0.695

AC:

105426

AN:

151770

Hom.:

37137

Cov.:

AF XY:

0.693

AC XY:

51385

AN XY:

74168

show subpopulations

African (AFR)

AF:

0.798

AC:

33056

AN:

41414

American (AMR)

AF:

0.576

AC:

8783

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.581

AC:

2015

AN:

3468

East Asian (EAS)

AF:

0.806

AC:

4154

AN:

5154

South Asian (SAS)

AF:

0.582

AC:

2794

AN:

4802

European-Finnish (FIN)

AF:

0.739

AC:

7771

AN:

10522

Middle Eastern (MID)

AF:

0.639

AC:

188

AN:

294

European-Non Finnish (NFE)

AF:

0.661

AC:

44851

AN:

67848

Other (OTH)

AF:

0.665

AC:

1401

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1551

3101

4652

6202

7753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.663

Hom.:

31524

Bravo

AF:

0.688

TwinsUK

AF:

0.680

AC:

2521

ALSPAC

AF:

0.682

AC:

2629

ESP6500AA

AF:

0.799

AC:

3522

ESP6500EA

AF:

0.650

AC:

5593

ExAC

AF:

0.658

AC:

79931

EpiCase

AF:

0.648

EpiControl

AF:

0.645

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26814133, 29105529) -

Jul 26, 2017

Athena Diagnostics

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

- -

not specified

Benign:2

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.Lys578Glu in exon 16 of CLCNKB: This variant is not expected to have clinical significance because it has been identified in 79.60% (8227/10336) of African ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs2275166). -

Dec 17, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

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

0.051

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

4.1

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.22

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.0087

T;T;T

MetaRNN

Benign

0.0000056

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.6

N;.;.

PhyloP100

1.0

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.16

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.032

MPC

0.19

ClinPred

0.0013

GERP RS

1.4

Varity_R

0.090

gMVP

0.42

Mutation Taster

=97/3

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