NM_000085.5:c.876T>C

Variant names:

• chr1-16049824-T-C
• rs7368151
• NM_000085.5:c.876T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000085.5(CLCNKB):​c.876T>C​(p.Cys292Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.922 in 1,613,546 control chromosomes in the GnomAD database, including 691,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (55003 hom., cov: 30)
  • Exomes 𝑓: 0.93 (636872 hom.)
• Consequence: CLCNKB NM_000085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.66
• Publications: 19 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-16049824-T-C is Benign according to our data. Variant chr1-16049824-T-C is described in ClinVar as Benign. ClinVar VariationId is 377683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.876T>C	p.Cys292Cys	synonymous	Exon 10 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.369T>C	p.Cys123Cys	synonymous	Exon 3 of 13	NP_001159417.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.876T>C	p.Cys292Cys	synonymous	Exon 10 of 20	ENSP00000364831.5
	CLCNKB	ENST00000682338.1		c.876T>C	p.Cys292Cys	synonymous	Exon 12 of 22	ENSP00000507062.1
	CLCNKB	ENST00000682793.1		c.876T>C	p.Cys292Cys	synonymous	Exon 10 of 20	ENSP00000506910.1

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126590 AN: 151652 Hom.: 54977 Cov.: 30

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.906

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.924

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.857

GnomAD2 exomes AF: 0.917 AC: 230454 AN: 251368 AF XY: 0.922

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.948

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.923

Gnomad NFE exome AF: 0.943

Gnomad OTH exome AF: 0.918

GnomAD4 exome AF: 0.931 AC: 1361297 AN: 1461776 Hom.: 636872 Cov.: 63 AF XY: 0.932 AC XY: 677745 AN XY: 727188

African (AFR) AF: 0.547 AC: 18305 AN: 33476

American (AMR) AF: 0.941 AC: 42099 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 23151 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39686 AN: 39700

South Asian (SAS) AF: 0.926 AC: 79869 AN: 86256

European-Finnish (FIN) AF: 0.923 AC: 49303 AN: 53420

Middle Eastern (MID) AF: 0.878 AC: 5067 AN: 5768

European-Non Finnish (NFE) AF: 0.943 AC: 1048740 AN: 1111914

Other (OTH) AF: 0.912 AC: 55077 AN: 60390

GnomAD4 genome AF: 0.835 AC: 126663 AN: 151770 Hom.: 55003 Cov.: 30 AF XY: 0.837 AC XY: 62076 AN XY: 74154

African (AFR) AF: 0.570 AC: 23513 AN: 41274

American (AMR) AF: 0.907 AC: 13843 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3061 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5125 AN: 5128

South Asian (SAS) AF: 0.937 AC: 4510 AN: 4812

European-Finnish (FIN) AF: 0.924 AC: 9758 AN: 10566

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.941 AC: 63947 AN: 67938

Other (OTH) AF: 0.859 AC: 1812 AN: 2110

Alfa AF: 0.887 Hom.: 52138

Bravo AF: 0.820

Asia WGS AF: 0.948 AC: 3295 AN: 3478

EpiCase AF: 0.936

EpiControl AF: 0.938

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 26, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 26, 2017

Athena Diagnostics

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.016
DANN	Benign	0.40
PhyloP100		-4.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7368151; hg19: chr1-16376319; COSMIC: COSV65161411; COSMIC: COSV65161411;