chr1-16046567-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000085.5(CLCNKB):c.262A>C(p.Ser88Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,614,072 control chromosomes in the GnomAD database, including 692 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 345 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 347 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0580

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Bartter disease type 3
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
Bartter disease type 4B
Inheritance: AR Classification: STRONG Submitted by: G2P
Bartter syndrome type 4
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Gitelman syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLCNKB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015670657).

BP6

Variant 1-16046567-A-C is Benign according to our data. Variant chr1-16046567-A-C is described in ClinVar as Benign. ClinVar VariationId is 447103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.262A>C	p.Ser88Arg	missense	Exon 4 of 20	NP_000076.2	P51801-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.262A>C	p.Ser88Arg	missense	Exon 4 of 20	ENSP00000364831.5	P51801-1
CLCNKB	ENST00000906263.1		c.316A>C	p.Ser106Arg	missense	Exon 5 of 21	ENSP00000576322.1
CLCNKB	ENST00000906270.1		c.316A>C	p.Ser106Arg	missense	Exon 5 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes

AF:

0.0355

AC:

5397

AN:

152126

Hom.:

344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.00923

AC:

2318

AN:

251230

AF XY:

0.00645

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00374

AC:

5464

AN:

1461828

Hom.:

347

Cov.:

AF XY:

0.00321

AC XY:

2336

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.134

AC:

4473

AN:

33478

American (AMR)

AF:

0.00677

AC:

303

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000243

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00539

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000128

AC:

142

AN:

1111996

Other (OTH)

AF:

0.00818

AC:

494

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

295

590

885

1180

1475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0356

AC:

5416

AN:

152244

Hom.:

345

Cov.:

AF XY:

0.0346

AC XY:

2573

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.124

AC:

5125

AN:

41494

American (AMR)

AF:

0.0131

AC:

201

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68014

Other (OTH)

AF:

0.0279

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

237

474

712

949

1186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0165

Hom.:

103

Bravo

AF:

0.0406

ESP6500AA

AF:

0.120

AC:

530

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0115

AC:

1392

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.33

CADD

Benign

8.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.5

PhyloP100

0.058

PROVEAN

Benign

-1.6

REVEL

Benign

0.18

Sift

Benign

0.043

Sift4G

Benign

0.35

Polyphen

0.13

Vest4

0.13

MutPred

0.24

Gain of MoRF binding (P = 0.0193)

MPC

0.036

ClinPred

0.0041

GERP RS

-1.1

Varity_R

0.065

gMVP

0.32

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over