chr1-16048569-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000375679.9(CLCNKB):c.642A>C(p.Ala214Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 151,746 control chromosomes in the GnomAD database, including 53,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 53688 hom., cov: 31)

Exomes 𝑓: 0.92 ( 614566 hom. )

Failed GnomAD Quality Control

Consequence

CLCNKB
ENST00000375679.9 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.93

Publications

10 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-16048569-A-C is Benign according to our data. Variant chr1-16048569-A-C is described in ClinVar as Benign. ClinVar VariationId is 504915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.93 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375679.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.642A>C	p.Ala214Ala	synonymous	Exon 7 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.-403A>C		upstream_gene	N/A	NP_001159417.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.642A>C	p.Ala214Ala	synonymous	Exon 7 of 20	ENSP00000364831.5
CLCNKB	ENST00000682338.1		c.642A>C	p.Ala214Ala	synonymous	Exon 9 of 22	ENSP00000507062.1
CLCNKB	ENST00000682793.1		c.642A>C	p.Ala214Ala	synonymous	Exon 7 of 20	ENSP00000506910.1

Frequencies

GnomAD3 genomes

AF:

0.826

AC:

125196

AN:

151630

Hom.:

53659

Cov.:

show subpopulations

Gnomad AFR

AF:

0.571

Gnomad AMI

AF:

0.913

Gnomad AMR

AF:

0.896

Gnomad ASJ

AF:

0.880

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.936

Gnomad FIN

AF:

0.918

Gnomad MID

AF:

0.896

Gnomad NFE

AF:

0.924

Gnomad OTH

AF:

0.848

GnomAD2 exomes

AF:

0.907

AC:

227189

AN:

250522

AF XY:

0.912

show subpopulations

Gnomad AFR exome

AF:

0.559

Gnomad AMR exome

AF:

0.939

Gnomad ASJ exome

AF:

0.890

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.919

Gnomad NFE exome

AF:

0.926

Gnomad OTH exome

AF:

0.906

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.915

AC:

1337179

AN:

1461102

Hom.:

614566

Cov.:

AF XY:

0.917

AC XY:

666207

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.549

AC:

18385

AN:

33458

American (AMR)

AF:

0.932

AC:

41642

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.884

AC:

23093

AN:

26130

East Asian (EAS)

AF:

1.00

AC:

39673

AN:

39690

South Asian (SAS)

AF:

0.924

AC:

79715

AN:

86238

European-Finnish (FIN)

AF:

0.918

AC:

48961

AN:

53340

Middle Eastern (MID)

AF:

0.876

AC:

4819

AN:

5504

European-Non Finnish (NFE)

AF:

0.923

AC:

1026650

AN:

1111704

Other (OTH)

AF:

0.899

AC:

54241

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

6639

13278

19917

26556

33195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21478

42956

64434

85912

107390

<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:

0.826

AC:

125274

AN:

151746

Hom.:

53688

Cov.:

AF XY:

0.829

AC XY:

61457

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.571

AC:

23556

AN:

41266

American (AMR)

AF:

0.896

AC:

13689

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.880

AC:

3051

AN:

3468

East Asian (EAS)

AF:

0.999

AC:

5110

AN:

5114

South Asian (SAS)

AF:

0.936

AC:

4511

AN:

4818

European-Finnish (FIN)

AF:

0.918

AC:

9726

AN:

10590

Middle Eastern (MID)

AF:

0.898

AC:

264

AN:

294

European-Non Finnish (NFE)

AF:

0.924

AC:

62749

AN:

67904

Other (OTH)

AF:

0.850

AC:

1793

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

899

1798

2698

3597

4496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.874

Hom.:

21208

Bravo

AF:

0.810

Asia WGS

AF:

0.948

AC:

3294

AN:

3478

EpiCase

AF:

0.917

EpiControl

AF:

0.922

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Bartter disease type 3 (1)

Bartter disease type 4B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.64

(source)

DANN

Benign

0.70

PhyloP100

-2.9

PromoterAI

0.077

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over