rs5255

Positions:

• chr1-16056471-C-T

Variant summary

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

The NM_000085.5(CLCNKB):​c.1979C>T​(p.Ser660Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,597,122 control chromosomes in the GnomAD database, including 129 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 0.015 (57 hom., cov: 29)
  • Exomes 𝑓: 0.0016 (72 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0910

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=0.0034534633).
• BP6: Variant 1-16056471-C-T is Benign according to our data. Variant chr1-16056471-C-T is described in ClinVar as [Benign]. Clinvar id is 447100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.1979C>T	p.Ser660Leu	missense_variant	19/20	ENST00000375679.9
CLCNKB	NM_001165945.2	c.1469C>T	p.Ser490Leu	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1979C>T	p.Ser660Leu	missense_variant	19/20	1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2254 AN: 150690 Hom.: 56 Cov.: 29

Gnomad AFR AF: 0.0528

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00357

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00921

GnomAD3 exomes AF: 0.00397 AC: 997 AN: 251220 Hom.: 21 AF XY: 0.00282 AC XY: 383 AN XY: 135788

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.00205

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: 0.000106

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00159 AC: 2306 AN: 1446308 Hom.: 72 Cov.: 35 AF XY: 0.00136 AC XY: 977 AN XY: 719176

Gnomad4 AFR exome AF: 0.0583

Gnomad4 AMR exome AF: 0.00251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000363

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.0150 AC: 2269 AN: 150814 Hom.: 57 Cov.: 29 AF XY: 0.0145 AC XY: 1067 AN XY: 73650

Gnomad4 AFR AF: 0.0530

Gnomad4 AMR AF: 0.00350

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.00911

Alfa AF: 0.0232 Hom.: 2363

Bravo AF: 0.0166

ESP6500AA AF: 0.0527 AC: 232

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00500 AC: 607

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0035	T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N;N
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.23
Sift	Benign	0.057	T;D
Sift4G	Benign	0.081	T;T
Polyphen		0.086	B;.
Vest4		0.32
MVP		0.85
MPC		0.14
ClinPred		0.023	T
GERP RS		3.9
Varity_R		0.20
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs5255; hg19: chr1-16382966; COSMIC: COSV99058380; COSMIC: COSV99058380;