Genetic Variant NM_000085.5:c.1741C>G (chr1-16053757-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000085.5(CLCNKB):c.1741C>G(p.Leu581Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L581L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.515

Publications

19 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16521594).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.1741C>G	p.Leu581Val	missense	Exon 16 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.1234C>G	p.Leu412Val	missense	Exon 9 of 13	NP_001159417.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.1741C>G	p.Leu581Val	missense	Exon 16 of 20	ENSP00000364831.5
CLCNKB	ENST00000906263.1		c.1795C>G	p.Leu599Val	missense	Exon 17 of 21	ENSP00000576322.1
CLCNKB	ENST00000906270.1		c.1795C>G	p.Leu599Val	missense	Exon 17 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151790

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151790

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74088

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41310

American (AMR)

AF:

0.0000655

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67914

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

7419

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.30

CADD

Benign

9.7

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.83

M_CAP

Benign

0.042

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

PhyloP100

0.52

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Benign

0.16

Sift4G

Benign

0.31

Polyphen

0.029

Vest4

0.14

MutPred

0.51

Gain of sheet (P = 0.1451)

MVP

0.72

MPC

0.14

ClinPred

0.15

GERP RS

1.6

Varity_R

0.12

gMVP

0.31

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over