Variant 1-16051724-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000085.5(CLCNKB):c.1312C>A(p.Arg438Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000233 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R438C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CLCNKB
NM_000085.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.99

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000085.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-16051724-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.1312C>A	p.Arg438Ser	missense_variant	14/20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 link	c.805C>A	p.Arg269Ser	missense_variant	7/13		NP_001159417.2	P51801-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.1312C>A	p.Arg438Ser	missense_variant	14/20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250988

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000148

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;D;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.3

.;M;.

PROVEAN

Pathogenic

-5.6

.;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D

Sift4G

Uncertain

0.049

D;D;D

Polyphen

0.99

.;D;.

Vest4

0.74

MutPred

0.81

.;Gain of glycosylation at R438 (P = 0.0148);.;

MVP

0.99

MPC

0.64

ClinPred

0.61

GERP RS

4.0

Varity_R

0.97

gMVP

0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over