1-16048499-C-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.577-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 151,938 control chromosomes in the GnomAD database, including 40,346 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 40346 hom., cov: 31)

Exomes 𝑓: 0.81 ( 478251 hom. )

Failed GnomAD Quality Control

Consequence

CLCNKB
NM_000085.5 splice_region, intron

Scores

Splicing: ADA: 0.00001950

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.322

Publications

14 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 (BayesDel_noAF=-0.82).

BP6

Variant 1-16048499-C-T is Benign according to our data. Variant chr1-16048499-C-T is described in ClinVar as Benign. ClinVar VariationId is 381050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.577-5C>T		splice_region_variant, intron_variant	Intron 6 of 19	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.577-5C>T		splice_region_variant, intron_variant	Intron 6 of 19	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.701

AC:

106363

AN:

151820

Hom.:

40322

Cov.:

show subpopulations

Gnomad AFR

AF:

0.387

Gnomad AMI

AF:

0.857

Gnomad AMR

AF:

0.827

Gnomad ASJ

AF:

0.806

Gnomad EAS

AF:

0.988

Gnomad SAS

AF:

0.889

Gnomad FIN

AF:

0.773

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.808

Gnomad OTH

AF:

0.739

GnomAD2 exomes

AF:

0.810

AC:

203324

AN:

250886

AF XY:

0.817

show subpopulations

Gnomad AFR exome

AF:

0.376

Gnomad AMR exome

AF:

0.899

Gnomad ASJ exome

AF:

0.824

Gnomad EAS exome

AF:

0.989

Gnomad FIN exome

AF:

0.763

Gnomad NFE exome

AF:

0.808

Gnomad OTH exome

AF:

0.811

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.805

AC:

1176330

AN:

1461204

Hom.:

478251

Cov.:

AF XY:

0.808

AC XY:

587645

AN XY:

726898

show subpopulations

African (AFR)

AF:

0.364

AC:

12175

AN:

33460

American (AMR)

AF:

0.888

AC:

39696

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.815

AC:

21294

AN:

26132

East Asian (EAS)

AF:

0.986

AC:

39136

AN:

39698

South Asian (SAS)

AF:

0.873

AC:

75272

AN:

86230

European-Finnish (FIN)

AF:

0.767

AC:

40927

AN:

53390

Middle Eastern (MID)

AF:

0.804

AC:

4422

AN:

5502

European-Non Finnish (NFE)

AF:

0.805

AC:

895441

AN:

1111744

Other (OTH)

AF:

0.795

AC:

47967

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

13584

27168

40752

54336

67920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20750

41500

62250

83000

103750

<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:

0.700

AC:

106410

AN:

151938

Hom.:

40346

Cov.:

AF XY:

0.707

AC XY:

52497

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.386

AC:

15992

AN:

41396

American (AMR)

AF:

0.827

AC:

12639

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.806

AC:

2793

AN:

3466

East Asian (EAS)

AF:

0.988

AC:

5074

AN:

5138

South Asian (SAS)

AF:

0.889

AC:

4287

AN:

4820

European-Finnish (FIN)

AF:

0.773

AC:

8184

AN:

10584

Middle Eastern (MID)

AF:

0.782

AC:

230

AN:

294

European-Non Finnish (NFE)

AF:

0.808

AC:

54870

AN:

67944

Other (OTH)

AF:

0.742

AC:

1565

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1282

2564

3846

5128

6410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

808

1616

2424

3232

4040

<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:

0.748

Hom.:

18567

Bravo

AF:

0.691

Asia WGS

AF:

0.899

AC:

3120

AN:

3476

EpiCase

AF:

0.814

EpiControl

AF:

0.816

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 12, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.577-5C>T in intron 6 of CLCNKB: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 98.97% (8553/8642) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs1889788). -

Bartter disease type 3

Benign:1

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.0

(source)

DANN

Benign

0.75

PhyloP100

-0.32

PromoterAI

0.048

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000020

dbscSNV1_RF

Benign

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over