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. 12/16 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

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 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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.656-105G>A		intron_variant	Intron 7 of 19	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 link	c.44G>A	p.Gly15Glu	missense_variant	Exon 1 of 13		NP_001159417.2	P51801-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.656-105G>A		intron_variant	Intron 7 of 19	1	NM_000085.5	ENSP00000364831.5		P51801-1

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

Gnomad4 AFR exome

AF:

0.245

AC:

8168

AN:

33302

Gnomad4 AMR exome

AF:

0.0378

AC:

1680

AN:

44424

Gnomad4 ASJ exome

AF:

0.0977

AC:

2538

AN:

25966

Gnomad4 EAS exome

AF:

0.000329

AC:

AN:

39556

Gnomad4 SAS exome

AF:

0.0259

AC:

2231

AN:

86030

Gnomad4 FIN exome

AF:

0.0718

AC:

3629

AN:

50564

Gnomad4 NFE exome

AF:

0.0439

AC:

48647

AN:

1107700

Gnomad4 Remaining exome

AF:

0.0601

AC:

3604

AN:

59960

Heterozygous variant carriers

3556

7111

10667

14222

17778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Gnomad4 AFR

AF:

0.233

AC:

0.233457

AN:

0.233457

Gnomad4 AMR

AF:

0.0622

AC:

0.0621978

AN:

0.0621978

Gnomad4 ASJ

AF:

0.104

AC:

0.103746

AN:

0.103746

Gnomad4 EAS

AF:

0.000387

AC:

0.000387447

AN:

0.000387447

Gnomad4 SAS

AF:

0.0219

AC:

0.0219462

AN:

0.0219462

Gnomad4 FIN

AF:

0.0712

AC:

0.0712267

AN:

0.0712267

Gnomad4 NFE

AF:

0.0434

AC:

0.0434476

AN:

0.0434476

Gnomad4 OTH

AF:

0.0824

AC:

0.0823864

AN:

0.0823864

Heterozygous variant carriers

620

1240

1860

2480

3100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

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.Gly15Glu in exon 1 of CLCNKB: This variant is not expected to have clinical si gnificance because it has been identified in 26.32% (2312/8784) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs11588392). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

4.3

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

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

Mutation Taster

=100/0

polymorphism (auto)

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

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