rs5256

Positions:

• chr1-16046567-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000375679.9(CLCNKB):​c.262A>C​(p.Ser88Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,614,072 control chromosomes in the GnomAD database, including 692 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.036 (345 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (347 hom.)
• Consequence: CLCNKB ENST00000375679.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0580

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015670657).
• BP6: Variant 1-16046567-A-C is Benign according to our data. Variant chr1-16046567-A-C is described in ClinVar as [Benign]. Clinvar id is 447103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5	c.262A>C	p.Ser88Arg	missense_variant	4/20	ENST00000375679.9	NP_000076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9	c.262A>C	p.Ser88Arg	missense_variant	4/20	1	NM_000085.5	ENSP00000364831	P4

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5397 AN: 152126 Hom.: 344 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.00923 AC: 2318 AN: 251230 Hom.: 165 AF XY: 0.00645 AC XY: 876 AN XY: 135864

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00374 AC: 5464 AN: 1461828 Hom.: 347 Cov.: 54 AF XY: 0.00321 AC XY: 2336 AN XY: 727218

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.00677

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.00818

GnomAD4 genome AF: 0.0356 AC: 5416 AN: 152244 Hom.: 345 Cov.: 33 AF XY: 0.0346 AC XY: 2573 AN XY: 74456

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0167 Hom.: 73

Bravo AF: 0.0406

ESP6500AA AF: 0.120 AC: 530

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0115 AC: 1392

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	.;M
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.6	.;N
REVEL	Benign	0.18
Sift	Benign	0.043	.;D
Sift4G	Benign	0.35	T;T
Polyphen		0.13	.;B
Vest4		0.13
MutPred		0.24		Gain of MoRF binding (P = 0.0193);Gain of MoRF binding (P = 0.0193);
MPC		0.036
ClinPred		0.0041	T
GERP RS		-1.1
Varity_R		0.065
gMVP		0.32

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: rs5256; hg19: chr1-16373062;