1-16053748-A-G

Position:

chr1-16053748-A-G

Variant summary

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

The NM_000085.5(CLCNKB):c.1732A>G(p.Lys578Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,610,920 control chromosomes in the GnomAD database, including 363,773 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 0.69 ( 37137 hom., cov: 32)

Exomes 𝑓: 0.67 ( 326636 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.01

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=5.6256567E-6).

BP6

Variant 1-16053748-A-G is Benign according to our data. Variant chr1-16053748-A-G is described in ClinVar as [Benign]. Clinvar id is 447096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16053748-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 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.1732A>G	p.Lys578Glu	missense_variant	16/20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 linkuse as main transcript	c.1225A>G	p.Lys409Glu	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.1732A>G	p.Lys578Glu	missense_variant	16/20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.695

AC:

105369

AN:

151652

Hom.:

37116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.799

Gnomad AMI

AF:

0.453

Gnomad AMR

AF:

0.577

Gnomad ASJ

AF:

0.581

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.739

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.661

Gnomad OTH

AF:

0.668

GnomAD3 exomes

AF:

0.653

AC:

163268

AN:

250048

Hom.:

54196

AF XY:

0.650

AC XY:

87976

AN XY:

135366

show subpopulations

Gnomad AFR exome

AF:

0.798

Gnomad AMR exome

AF:

0.518

Gnomad ASJ exome

AF:

0.582

Gnomad EAS exome

AF:

0.795

Gnomad SAS exome

AF:

0.583

Gnomad FIN exome

AF:

0.739

Gnomad NFE exome

AF:

0.659

Gnomad OTH exome

AF:

0.655

GnomAD4 exome

AF:

0.667

AC:

973531

AN:

1459150

Hom.:

326636

Cov.:

AF XY:

0.664

AC XY:

482151

AN XY:

725916

show subpopulations

Gnomad4 AFR exome

AF:

0.807

Gnomad4 AMR exome

AF:

0.524

Gnomad4 ASJ exome

AF:

0.589

Gnomad4 EAS exome

AF:

0.811

Gnomad4 SAS exome

AF:

0.583

Gnomad4 FIN exome

AF:

0.737

Gnomad4 NFE exome

AF:

0.669

Gnomad4 OTH exome

AF:

0.667

GnomAD4 genome

AF:

0.695

AC:

105426

AN:

151770

Hom.:

37137

Cov.:

AF XY:

0.693

AC XY:

51385

AN XY:

74168

show subpopulations

Gnomad4 AFR

AF:

0.798

Gnomad4 AMR

AF:

0.576

Gnomad4 ASJ

AF:

0.581

Gnomad4 EAS

AF:

0.806

Gnomad4 SAS

AF:

0.582

Gnomad4 FIN

AF:

0.739

Gnomad4 NFE

AF:

0.661

Gnomad4 OTH

AF:

0.665

Alfa

AF:

0.665

Hom.:

17395

Bravo

AF:

0.688

TwinsUK

AF:

0.680

AC:

2521

ALSPAC

AF:

0.682

AC:

2629

ESP6500AA

AF:

0.799

AC:

3522

ESP6500EA

AF:

0.650

AC:

5593

ExAC

AF:

0.658

AC:

79931

EpiCase

AF:

0.648

EpiControl

AF:

0.645

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 26814133, 29105529) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Lys578Glu in exon 16 of CLCNKB: This variant is not expected to have clinical significance because it has been identified in 79.60% (8227/10336) of African ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs2275166). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2021	- -

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

0.051

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

4.1

DANN

Benign

0.77

DEOGEN2

Benign

0.22

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.0087

T;T;T

MetaRNN

Benign

0.0000056

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.6

N;.;.

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.16

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.032

MPC

0.19

ClinPred

0.0013

GERP RS

1.4

Varity_R

0.090

gMVP

0.42

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

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