rs11588392

Variant names:

Variant summary

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

The NM_001165945.2(CLCNKB):c.44G>A(p.Gly15Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,604,684 control chromosomes in the GnomAD database, including 3,984 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.099 ( 1345 hom., cov: 34)

Exomes 𝑓: 0.049 ( 2639 hom. )

Consequence

CLCNKB
NM_001165945.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.259

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=0.005407542).

BP6

Variant 1-16049015-G-A is Benign according to our data. Variant chr1-16049015-G-A is described in ClinVar as Benign. ClinVar VariationId is 504913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165945.2. 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.656-105G>A		intron	N/A	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.44G>A	p.Gly15Glu	missense	Exon 1 of 13	NP_001159417.2	P51801-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.656-105G>A		intron	N/A	ENSP00000364831.5	P51801-1
CLCNKB	ENST00000375667.7	TSL:2	c.44G>A	p.Gly15Glu	missense	Exon 1 of 13	ENSP00000364819.3	P51801-2
CLCNKB	ENST00000906263.1		c.710-105G>A		intron	N/A	ENSP00000576322.1

Frequencies

GnomAD3 genomes

AF:

0.0988

AC:

15020

AN:

152040

Hom.:

1343

Cov.:

show subpopulations

Gnomad AFR

AF:

0.234

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0623

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0228

Gnomad FIN

AF:

0.0712

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0435

Gnomad OTH

AF:

0.0833

GnomAD2 exomes

AF:

0.0531

AC:

13017

AN:

245060

AF XY:

0.0499

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.0340

Gnomad ASJ exome

AF:

0.0917

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0719

Gnomad NFE exome

AF:

0.0422

Gnomad OTH exome

AF:

0.0558

GnomAD4 exome

AF:

0.0488

AC:

70823

AN:

1452526

Hom.:

2639

Cov.:

AF XY:

0.0476

AC XY:

34375

AN XY:

721706

show subpopulations

African (AFR)

AF:

0.245

AC:

8168

AN:

33302

American (AMR)

AF:

0.0378

AC:

1680

AN:

44424

Ashkenazi Jewish (ASJ)

AF:

0.0977

AC:

2538

AN:

25966

East Asian (EAS)

AF:

0.000329

AC:

AN:

39556

South Asian (SAS)

AF:

0.0259

AC:

2231

AN:

86030

European-Finnish (FIN)

AF:

0.0718

AC:

3629

AN:

50564

Middle Eastern (MID)

AF:

0.0623

AC:

313

AN:

5024

European-Non Finnish (NFE)

AF:

0.0439

AC:

48647

AN:

1107700

Other (OTH)

AF:

0.0601

AC:

3604

AN:

59960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

3556

7111

10667

14222

17778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2000

4000

6000

8000

10000

<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:

0.0988

AC:

15036

AN:

152158

Hom.:

1345

Cov.:

AF XY:

0.0972

AC XY:

7228

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.233

AC:

9681

AN:

41468

American (AMR)

AF:

0.0622

AC:

952

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.104

AC:

360

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5162

South Asian (SAS)

AF:

0.0219

AC:

106

AN:

4830

European-Finnish (FIN)

AF:

0.0712

AC:

756

AN:

10614

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0434

AC:

2954

AN:

67990

Other (OTH)

AF:

0.0824

AC:

174

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

620

1240

1860

2480

3100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0571

Hom.:

481

Bravo

AF:

0.105

TwinsUK

AF:

0.0453

AC:

168

ALSPAC

AF:

0.0522

AC:

201

ESP6500AA

AF:

0.214

AC:

296

ESP6500EA

AF:

0.0469

AC:

149

ExAC

AF:

0.0545

AC:

6615

Asia WGS

AF:

0.0230

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

4.3

(source)

DANN

Benign

0.93

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.1

PhyloP100

-0.26

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.044

ClinPred

0.012

GERP RS

-4.7

PromoterAI

0.037

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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