1-16049696-C-T

Position:

chr1-16049696-C-T

Variant summary

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

The NM_000085.5(CLCNKB):c.860C>T(p.Ala287Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 150,922 control chromosomes in the GnomAD database, including 54,696 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A287M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.83 ( 54696 hom., cov: 26)

Exomes 𝑓: 0.93 ( 635261 hom. )

Failed GnomAD Quality Control

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.104

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.2536123E-7).

BP6

Variant 1-16049696-C-T is Benign according to our data. Variant chr1-16049696-C-T is described in ClinVar as [Benign]. Clinvar id is 447108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16049696-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.860C>T	p.Ala287Val	missense_variant	9/20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 link	c.353C>T	p.Ala118Val	missense_variant	2/13		NP_001159417.2	P51801-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.860C>T	p.Ala287Val	missense_variant	9/20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.835

AC:

125886

AN:

150804

Hom.:

54670

Cov.:

show subpopulations

Gnomad AFR

AF:

0.569

Gnomad AMI

AF:

0.913

Gnomad AMR

AF:

0.907

Gnomad ASJ

AF:

0.882

Gnomad EAS

AF:

0.998

Gnomad SAS

AF:

0.936

Gnomad FIN

AF:

0.923

Gnomad MID

AF:

0.896

Gnomad NFE

AF:

0.941

Gnomad OTH

AF:

0.856

GnomAD3 exomes

AF:

0.925

AC:

222892

AN:

241002

Hom.:

104557

AF XY:

0.929

AC XY:

121699

AN XY:

130996

show subpopulations

Gnomad AFR exome

AF:

0.557

Gnomad AMR exome

AF:

0.960

Gnomad ASJ exome

AF:

0.899

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.933

Gnomad FIN exome

AF:

0.932

Gnomad NFE exome

AF:

0.948

Gnomad OTH exome

AF:

0.929

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.931

AC:

1357536

AN:

1457498

Hom.:

635261

Cov.:

AF XY:

0.932

AC XY:

676035

AN XY:

725266

show subpopulations

Gnomad4 AFR exome

AF:

0.546

Gnomad4 AMR exome

AF:

0.942

Gnomad4 ASJ exome

AF:

0.886

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.925

Gnomad4 FIN exome

AF:

0.923

Gnomad4 NFE exome

AF:

0.943

Gnomad4 OTH exome

AF:

0.912

GnomAD4 genome

AF:

0.835

AC:

125959

AN:

150922

Hom.:

54696

Cov.:

AF XY:

0.837

AC XY:

61653

AN XY:

73646

show subpopulations

Gnomad4 AFR

AF:

0.569

Gnomad4 AMR

AF:

0.907

Gnomad4 ASJ

AF:

0.882

Gnomad4 EAS

AF:

0.998

Gnomad4 SAS

AF:

0.937

Gnomad4 FIN

AF:

0.923

Gnomad4 NFE

AF:

0.941

Gnomad4 OTH

AF:

0.858

Alfa

AF:

0.887

Hom.:

10155

Bravo

AF:

0.820

ExAC

AF:

0.909

AC:

110055

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
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	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ala287Val in exon 9 of CLCNKB: This variant is not expected to have clinical s ignificance because it has been identified in 99.86% (8047/8058) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs7367494). -
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+	-	- -

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

0.061

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.093

DANN

Benign

0.21

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.14

T;T

MetaRNN

Benign

9.3e-7

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.35

N;.

PROVEAN

Benign

1.6

N;N

REVEL

Benign

0.22

Sift

Benign

0.84

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;.

Vest4

0.054

MPC

1.2

ClinPred

0.0022

GERP RS

-6.5

Varity_R

0.031

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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