1-16052230-A-T

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.1441A>T(p.Thr481Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,612,846 control chromosomes in the GnomAD database, including 11,747 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1691 hom., cov: 33)

Exomes 𝑓: 0.11 ( 10056 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.954

Publications

24 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: Orphanet, Labcorp Genetics (formerly Invitae)
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=0.0018473566).

BP6

Variant 1-16052230-A-T is Benign according to our data. Variant chr1-16052230-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 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.1441A>T	p.Thr481Ser	missense	Exon 15 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.934A>T	p.Thr312Ser	missense	Exon 8 of 13	NP_001159417.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.1441A>T	p.Thr481Ser	missense	Exon 15 of 20	ENSP00000364831.5
CLCNKB	ENST00000906263.1		c.1495A>T	p.Thr499Ser	missense	Exon 16 of 21	ENSP00000576322.1
CLCNKB	ENST00000906270.1		c.1495A>T	p.Thr499Ser	missense	Exon 16 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20103

AN:

152102

Hom.:

1675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.215

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0752

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.0114

Gnomad SAS

AF:

0.0442

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.118

GnomAD2 exomes

AF:

0.0956

AC:

23916

AN:

250126

AF XY:

0.0932

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.0480

Gnomad ASJ exome

AF:

0.0505

Gnomad EAS exome

AF:

0.0105

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.0964

GnomAD4 exome

AF:

0.112

AC:

163065

AN:

1460626

Hom.:

10056

Cov.:

AF XY:

0.109

AC XY:

79213

AN XY:

726596

show subpopulations

African (AFR)

AF:

0.219

AC:

7344

AN:

33466

American (AMR)

AF:

0.0522

AC:

2332

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0533

AC:

1393

AN:

26134

East Asian (EAS)

AF:

0.0137

AC:

545

AN:

39700

South Asian (SAS)

AF:

0.0488

AC:

4212

AN:

86250

European-Finnish (FIN)

AF:

0.126

AC:

6631

AN:

52478

Middle Eastern (MID)

AF:

0.0732

AC:

420

AN:

5736

European-Non Finnish (NFE)

AF:

0.120

AC:

133782

AN:

1111788

Other (OTH)

AF:

0.106

AC:

6406

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

9432

18864

28296

37728

47160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4790

9580

14370

19160

23950

<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:

0.132

AC:

20160

AN:

152220

Hom.:

1691

Cov.:

AF XY:

0.129

AC XY:

9569

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.216

AC:

8971

AN:

41538

American (AMR)

AF:

0.0751

AC:

1148

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

197

AN:

3468

East Asian (EAS)

AF:

0.0116

AC:

AN:

5176

South Asian (SAS)

AF:

0.0440

AC:

212

AN:

4818

European-Finnish (FIN)

AF:

0.121

AC:

1283

AN:

10604

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.117

AC:

7956

AN:

68000

Other (OTH)

AF:

0.117

AC:

247

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

867

1734

2602

3469

4336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.116

Hom.:

362

Bravo

AF:

0.131

TwinsUK

AF:

0.126

AC:

466

ALSPAC

AF:

0.129

AC:

496

ESP6500AA

AF:

0.211

AC:

928

ESP6500EA

AF:

0.110

AC:

942

ExAC

AF:

0.101

AC:

12272

Asia WGS

AF:

0.0550

AC:

191

AN:

3478

EpiCase

AF:

0.108

EpiControl

AF:

0.107

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.91

PhyloP100

0.95

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.24

Sift

Benign

0.27

Sift4G

Benign

0.38

Polyphen

0.058

Vest4

0.22

MutPred

0.27

Loss of helix (P = 0.0196)

MPC

0.18

ClinPred

0.031

GERP RS

-3.3

PromoterAI

-0.016

Neutral

(source)

Varity_R

0.16

gMVP

0.43

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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