rs143663847

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000085.5(CLCNKB):c.1877G>A(p.Cys626Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,758 control chromosomes in the GnomAD database, including 552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 69 hom., cov: 33)

Exomes 𝑓: 0.014 ( 483 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.98

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 links:

CLCNKB (HGNC:):

CLCNKB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029669702).

BP6

Variant 1-16055706-G-A is Benign according to our data. Variant chr1-16055706-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 402541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16055706-G-A is described in Lovd as [Benign]. Variant chr1-16055706-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5 linkuse as main transcript	c.1877G>A	p.Cys626Tyr	missense_variant	18/20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 linkuse as main transcript	c.1367G>A	p.Cys456Tyr	missense_variant	11/13		NP_001159417.2	P51801-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 linkuse as main transcript	c.1877G>A	p.Cys626Tyr	missense_variant	18/20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2261

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00355

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0751

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.00753

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0257

AC:

6453

AN:

251146

Hom.:

304

AF XY:

0.0222

AC XY:

3018

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0146

Gnomad FIN exome

AF:

0.00665

Gnomad NFE exome

AF:

0.0116

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0144

AC:

21026

AN:

1461462

Hom.:

483

Cov.:

AF XY:

0.0140

AC XY:

10207

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.00164

Gnomad4 AMR exome

AF:

0.121

Gnomad4 ASJ exome

AF:

0.00383

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0160

Gnomad4 FIN exome

AF:

0.00764

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.0149

AC:

2269

AN:

152296

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1169

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00354

Gnomad4 AMR

AF:

0.0756

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.00753

Gnomad4 NFE

AF:

0.0112

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.0217

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.0228

AC:

2767

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2020	This variant is associated with the following publications: (PMID: 28381550, 27535533, 21415153) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 35/2178=1.6% -

Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The p.Cys626Tyr variant in CLCNKB has been identified in an individual from a patient cohort with suspected Gitelman Syndrome (PMID: 21415153). However, this variant is classified as benign for Bartter syndrome because it has been identified in >5% of Latino chromosomes by ExAC (http://gnomad.broadinstitute.org/). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.8

M;.;.

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.0030

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.35

MPC

0.79

ClinPred

0.022

GERP RS

4.7

Varity_R

0.69

gMVP

0.44

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over