1-16049824-T-C

Position:

• chr1-16049824-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 377683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16049824-T-C is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5	c.876T>C	p.Cys292Cys	synonymous_variant	10/20	ENST00000375679.9	NP_000076.2
CLCNKB	NM_001165945.2	c.369T>C	p.Cys123Cys	synonymous_variant	3/13		NP_001159417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9	c.876T>C	p.Cys292Cys	synonymous_variant	10/20	1	NM_000085.5	ENSP00000364831.5

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

GnomAD3 exomes AF: 0.917 AC: 230454 AN: 251368 Hom.: 106922 AF XY: 0.922 AC XY: 125220 AN XY: 135840

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 SAS exome AF: 0.927

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

Gnomad4 AFR exome AF: 0.547

Gnomad4 AMR exome AF: 0.941

Gnomad4 ASJ exome AF: 0.886

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.926

Gnomad4 FIN exome AF: 0.923

Gnomad4 NFE exome AF: 0.943

Gnomad4 OTH exome AF: 0.912

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

Gnomad4 AFR AF: 0.570

Gnomad4 AMR AF: 0.907

Gnomad4 ASJ AF: 0.882

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.937

Gnomad4 FIN AF: 0.924

Gnomad4 NFE AF: 0.941

Gnomad4 OTH AF: 0.859

Alfa AF: 0.887 Hom.: 38799

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2015	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bartter disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Bartter disease type 4B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.016
DANN	Benign	0.40

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

Other links and lift over

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