chr1-16053701-T-C

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.1685T>C(p.Met562Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.96 in 1,613,870 control chromosomes in the GnomAD database, including 747,019 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 (★★).

Frequency

Genomes: 𝑓 0.89 ( 61143 hom., cov: 32)

Exomes 𝑓: 0.97 ( 685876 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.34

Publications

34 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=8.2137257E-7).

BP6

Variant 1-16053701-T-C is Benign according to our data. Variant chr1-16053701-T-C is described in ClinVar as Benign. ClinVar VariationId is 447094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.1685T>C	p.Met562Thr	missense_variant	Exon 16 of 20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 link	c.1178T>C	p.Met393Thr	missense_variant	Exon 9 of 13		NP_001159417.2	P51801-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.1685T>C	p.Met562Thr	missense_variant	Exon 16 of 20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.888

AC:

134991

AN:

152028

Hom.:

61122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.696

Gnomad AMI

AF:

0.997

Gnomad AMR

AF:

0.929

Gnomad ASJ

AF:

0.947

Gnomad EAS

AF:

0.820

Gnomad SAS

AF:

0.919

Gnomad FIN

AF:

0.939

Gnomad MID

AF:

0.962

Gnomad NFE

AF:

0.985

Gnomad OTH

AF:

0.911

GnomAD2 exomes

AF:

0.935

AC:

234686

AN:

251092

AF XY:

0.941

show subpopulations

Gnomad AFR exome

AF:

0.686

Gnomad AMR exome

AF:

0.948

Gnomad ASJ exome

AF:

0.952

Gnomad EAS exome

AF:

0.808

Gnomad FIN exome

AF:

0.938

Gnomad NFE exome

AF:

0.984

Gnomad OTH exome

AF:

0.953

GnomAD4 exome

AF:

0.967

AC:

1413473

AN:

1461724

Hom.:

685876

Cov.:

AF XY:

0.967

AC XY:

703266

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.679

AC:

22731

AN:

33480

American (AMR)

AF:

0.943

AC:

42157

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.953

AC:

24899

AN:

26136

East Asian (EAS)

AF:

0.818

AC:

32479

AN:

39700

South Asian (SAS)

AF:

0.932

AC:

80408

AN:

86252

European-Finnish (FIN)

AF:

0.936

AC:

49863

AN:

53270

Middle Eastern (MID)

AF:

0.968

AC:

5585

AN:

5768

European-Non Finnish (NFE)

AF:

0.988

AC:

1098270

AN:

1112006

Other (OTH)

AF:

0.945

AC:

57081

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2568

5137

7705

10274

12842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21624

43248

64872

86496

108120

<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:

0.888

AC:

135058

AN:

152146

Hom.:

61143

Cov.:

AF XY:

0.885

AC XY:

65849

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.696

AC:

28864

AN:

41474

American (AMR)

AF:

0.928

AC:

14199

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.947

AC:

3287

AN:

3472

East Asian (EAS)

AF:

0.820

AC:

4232

AN:

5164

South Asian (SAS)

AF:

0.919

AC:

4430

AN:

4818

European-Finnish (FIN)

AF:

0.939

AC:

9959

AN:

10602

Middle Eastern (MID)

AF:

0.959

AC:

282

AN:

294

European-Non Finnish (NFE)

AF:

0.985

AC:

66976

AN:

68002

Other (OTH)

AF:

0.910

AC:

1920

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

636

1273

1909

2546

3182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.957

Hom.:

92580

Bravo

AF:

0.877

TwinsUK

AF:

0.989

AC:

3668

ALSPAC

AF:

0.988

AC:

3809

ESP6500AA

AF:

0.701

AC:

3087

ESP6500EA

AF:

0.984

AC:

8462

ExAC

AF:

0.931

AC:

112995

Asia WGS

AF:

0.817

AC:

2840

AN:

3478

EpiCase

AF:

0.984

EpiControl

AF:

0.986

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 26, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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.Met562Thr in exon 16 of CLCNKB: This variant is not expected to have clinical significance because it has been identified in 98.02% (65150/66466) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs5253). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), 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

0.056

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.017

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.23

T;.;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.015

T;T;T

MetaRNN

Benign

8.2e-7

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.94

N;.;.

PhyloP100

-1.3

PROVEAN

Benign

0.22

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.87

T;T;T

Sift4G

Benign

0.70

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.016

MPC

0.15

ClinPred

0.0096

GERP RS

-3.7

Varity_R

0.049

gMVP

0.34

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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