1-16048568-C-G

Variant names:

Variant summary

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

The NM_000085.5(CLCNKB):c.641C>G(p.Ala214Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 151,752 control chromosomes in the GnomAD database, including 53,689 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A214A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.83 ( 53689 hom., cov: 31)

Exomes 𝑓: 0.92 ( 614572 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: -0.228

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.2906515E-6).

BP6

Variant 1-16048568-C-G is Benign according to our data. Variant chr1-16048568-C-G is described in ClinVar as [Benign]. Clinvar id is 504916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16048568-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.641C>G	p.Ala214Gly	missense_variant	Exon 7 of 20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 link	c.-404C>G		upstream_gene_variant			NP_001159417.2	P51801-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.641C>G	p.Ala214Gly	missense_variant	Exon 7 of 20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.826

AC:

125197

AN:

151636

Hom.:

53660

Cov.:

show subpopulations

Gnomad AFR

AF:

0.571

Gnomad AMI

AF:

0.913

Gnomad AMR

AF:

0.896

Gnomad ASJ

AF:

0.880

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.936

Gnomad FIN

AF:

0.918

Gnomad MID

AF:

0.896

Gnomad NFE

AF:

0.924

Gnomad OTH

AF:

0.848

GnomAD3 exomes

AF:

0.907

AC:

227210

AN:

250534

Hom.:

104236

AF XY:

0.912

AC XY:

123647

AN XY:

135542

show subpopulations

Gnomad AFR exome

AF:

0.559

Gnomad AMR exome

AF:

0.939

Gnomad ASJ exome

AF:

0.890

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.926

Gnomad FIN exome

AF:

0.919

Gnomad NFE exome

AF:

0.926

Gnomad OTH exome

AF:

0.906

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.915

AC:

1337185

AN:

1461102

Hom.:

614572

Cov.:

AF XY:

0.917

AC XY:

666217

AN XY:

726860

show subpopulations

Gnomad4 AFR exome

AF:

0.549

Gnomad4 AMR exome

AF:

0.932

Gnomad4 ASJ exome

AF:

0.884

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.924

Gnomad4 FIN exome

AF:

0.918

Gnomad4 NFE exome

AF:

0.923

Gnomad4 OTH exome

AF:

0.899

GnomAD4 genome

AF:

0.826

AC:

125275

AN:

151752

Hom.:

53689

Cov.:

AF XY:

0.829

AC XY:

61461

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.571

Gnomad4 AMR

AF:

0.896

Gnomad4 ASJ

AF:

0.880

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.936

Gnomad4 FIN

AF:

0.918

Gnomad4 NFE

AF:

0.924

Gnomad4 OTH

AF:

0.850

Alfa

AF:

0.898

Hom.:

15638

Bravo

AF:

0.810

ExAC

AF:

0.900

AC:

109279

Asia WGS

AF:

0.948

AC:

3294

AN:

3478

EpiCase

AF:

0.917

EpiControl

AF:

0.922

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala214Gly in exon 7 of CLCNKB: This variant is not expected to have clinical s ignificance because it has been identified in 99.93% (8630/8636) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs1889789). -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bartter disease type 3

Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bartter disease type 4B

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

5.5

DANN

Benign

0.75

DEOGEN2

Benign

0.23

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0000023

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.2

PROVEAN

Benign

0.82

REVEL

Benign

0.21

Sift

Benign

0.69

Sift4G

Benign

0.86

Polyphen

0.0

Vest4

0.36

MPC

1.2

ClinPred

0.00043

GERP RS

2.7

Varity_R

0.038

gMVP

0.26

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