rs5253

Positions:

chr1-16053701-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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

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=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 id is 447094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16053701-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5 linkuse as main transcript	c.1685T>C	p.Met562Thr	missense_variant	16/20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 linkuse as main transcript	c.1178T>C	p.Met393Thr	missense_variant	9/13		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.1685T>C	p.Met562Thr	missense_variant	16/20	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

GnomAD3 exomes

AF:

0.935

AC:

234686

AN:

251092

Hom.:

110523

AF XY:

0.941

AC XY:

127782

AN XY:

135846

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 SAS exome

AF:

0.932

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

Gnomad4 AFR exome

AF:

0.679

Gnomad4 AMR exome

AF:

0.943

Gnomad4 ASJ exome

AF:

0.953

Gnomad4 EAS exome

AF:

0.818

Gnomad4 SAS exome

AF:

0.932

Gnomad4 FIN exome

AF:

0.936

Gnomad4 NFE exome

AF:

0.988

Gnomad4 OTH exome

AF:

0.945

GnomAD4 genome

AF:

0.888

AC:

135058

AN:

152146

Hom.:

61143

Cov.:

AF XY:

0.885

AC XY:

65849

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.696

Gnomad4 AMR

AF:

0.928

Gnomad4 ASJ

AF:

0.947

Gnomad4 EAS

AF:

0.820

Gnomad4 SAS

AF:

0.919

Gnomad4 FIN

AF:

0.939

Gnomad4 NFE

AF:

0.985

Gnomad4 OTH

AF:

0.910

Alfa

AF:

0.958

Hom.:

62547

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Athena Diagnostics	Jul 26, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

0.017

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;.;.

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

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

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