1-16051724-C-T

Position:

chr1-16051724-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000085.5(CLCNKB):c.1312C>T(p.Arg438Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R438H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 3.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000085.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-16051725-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2055600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 1-16051724-C-T is Pathogenic according to our data. Variant chr1-16051724-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.1312C>T	p.Arg438Cys	missense_variant	14/20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 link	c.805C>T	p.Arg269Cys	missense_variant	7/13		NP_001159417.2	P51801-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.1312C>T	p.Arg438Cys	missense_variant	14/20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250988

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.0000381

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bartter disease type 3

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1997	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jul 30, 2024	ACMG codes: PS3_Strong, PS4_Strong, PM2_Moderate, PP3_Supporting, PP4_Supporting -

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 438 of the CLCNKB protein (p.Arg438Cys). This variant is present in population databases (rs121909133, gnomAD 0.007%). This missense change has been observed in individuals with Bartter syndrome (PMID: 9326936, 21631963, 28381550, 31115572). ClinVar contains an entry for this variant (Variation ID: 7593). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCNKB protein function. Experimental studies have shown that this missense change affects CLCNKB function (PMID: 10831588, 11734858). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg438 amino acid residue in CLCNKB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10906158, 23703872, 28381550, 31115572, 32857947). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2018	- -
Uncertain significance, no assertion criteria provided	literature only	Martin Pollak Laboratory, Beth Israel Deaconess Medical Center	-	- -

Bartter disease type 3;C4310805:Bartter disease type 4B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

.;D;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

.;H;.

PROVEAN

Pathogenic

-7.5

.;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.97

MVP

0.98

MPC

0.70

ClinPred

1.0

GERP RS

4.0

Varity_R

0.85

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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