rs144517772

Positions:

• chr1-16049164-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000085.5(CLCNKB):​c.700T>C​(p.Trp234Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,613,402 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00786981).
• BP6: Variant 1-16049164-T-C is Benign according to our data. Variant chr1-16049164-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523320.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.700T>C	p.Trp234Arg	missense_variant	8/20	ENST00000375679.9
CLCNKB	NM_001165945.2	c.193T>C	p.Trp65Arg	missense_variant	1/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.700T>C	p.Trp234Arg	missense_variant	8/20	1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152176 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000430 AC: 108 AN: 251436 Hom.: 0 AF XY: 0.000397 AC XY: 54 AN XY: 135890

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000282 AC: 412 AN: 1461108 Hom.: 1 Cov.: 48 AF XY: 0.000292 AC XY: 212 AN XY: 726766

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152294 Hom.: 1 Cov.: 34 AF XY: 0.000752 AC XY: 56 AN XY: 74480

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000573 Hom.: 0

Bravo AF: 0.000884

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000511 AC: 62

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bartter disease type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 12, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: No criteria apply. -

Hematuria;C0033687:Proteinuria Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.77	N;.
MutationTaster	Benign	0.75	D;D
PROVEAN	Benign	2.8	N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.29
MutPred		0.55		Gain of catalytic residue at W234 (P = 0.0566);.;
MVP		0.83
MPC		1.9
ClinPred		0.012	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs144517772; hg19: chr1-16375659;