Genetic Variant CLCNKB:c.-8+104T>C (chr1-16043984-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000085.5(CLCNKB):c.-8+104T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 146,190 control chromosomes in the GnomAD database, including 18,725 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 18434 hom., cov: 25)

Exomes 𝑓: 0.47 ( 291 hom. )

Consequence

CLCNKB
NM_000085.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.54

Publications

2 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.-8+104T>C		intron_variant	Intron 1 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.-8+104T>C		intron_variant	Intron 1 of 19	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.506

AC:

72826

AN:

143818

Hom.:

18423

Cov.:

show subpopulations

Gnomad AFR

AF:

0.453

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.476

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.718

Gnomad SAS

AF:

0.464

Gnomad FIN

AF:

0.524

Gnomad MID

AF:

0.520

Gnomad NFE

AF:

0.532

Gnomad OTH

AF:

0.508

GnomAD4 exome

AF:

0.466

AC:

1058

AN:

2268

Hom.:

291

AF XY:

0.460

AC XY:

556

AN XY:

1210

show subpopulations

African (AFR)

AF:

0.305

AC:

AN:

American (AMR)

AF:

0.420

AC:

210

AN:

500

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

AN:

East Asian (EAS)

AF:

0.745

AC:

AN:

102

South Asian (SAS)

AF:

0.422

AC:

AN:

192

European-Finnish (FIN)

AF:

0.386

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.481

AC:

585

AN:

1216

Other (OTH)

AF:

0.510

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

118

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.506

AC:

72867

AN:

143922

Hom.:

18434

Cov.:

AF XY:

0.505

AC XY:

35199

AN XY:

69764

show subpopulations

African (AFR)

AF:

0.453

AC:

17187

AN:

37970

American (AMR)

AF:

0.475

AC:

6823

AN:

14364

Ashkenazi Jewish (ASJ)

AF:

0.454

AC:

1533

AN:

3374

East Asian (EAS)

AF:

0.718

AC:

3572

AN:

4976

South Asian (SAS)

AF:

0.464

AC:

2096

AN:

4518

European-Finnish (FIN)

AF:

0.524

AC:

4942

AN:

9432

Middle Eastern (MID)

AF:

0.535

AC:

152

AN:

284

European-Non Finnish (NFE)

AF:

0.532

AC:

35201

AN:

66130

Other (OTH)

AF:

0.506

AC:

1016

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

1275

2549

3824

5098

6373

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.393

Hom.:

1582

Bravo

AF:

0.484

Asia WGS

AF:

0.518

AC:

1800

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.057

(source)

DANN

Benign

0.28

PhyloP100

-2.5

PromoterAI

0.018

Neutral

(source)

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over