rs35480349

Positions:

• chr1-16050613-G-C
• chr1-16050613-G-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.1053+13G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,612,578 control chromosomes in the GnomAD database, including 46,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3664 hom., cov: 33)
  • Exomes 𝑓: 0.23 (42843 hom.)
• Consequence: CLCNKB NM_000085.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.49

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 (BayesDel_noAF=-0.86).
• BP6: Variant 1-16050613-G-C is Benign according to our data. Variant chr1-16050613-G-C is described in ClinVar as [Benign]. Clinvar id is 504914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16050613-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5	c.1053+13G>C		intron_variant		ENST00000375679.9	NP_000076.2
CLCNKB	NM_001165945.2	c.546+13G>C		intron_variant			NP_001159417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1053+13G>C		intron_variant		1	NM_000085.5	ENSP00000364831	P4

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29175 AN: 152058 Hom.: 3653 Cov.: 33

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.239 AC: 59848 AN: 250624 Hom.: 8422 AF XY: 0.243 AC XY: 32976 AN XY: 135538

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.0111

Gnomad SAS exome AF: 0.312

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.234 AC: 342230 AN: 1460402 Hom.: 42843 Cov.: 34 AF XY: 0.238 AC XY: 172649 AN XY: 726578

Gnomad4 AFR exome AF: 0.0395

Gnomad4 AMR exome AF: 0.347

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.00620

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.210

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.227

GnomAD4 genome AF: 0.192 AC: 29197 AN: 152176 Hom.: 3664 Cov.: 33 AF XY: 0.194 AC XY: 14458 AN XY: 74398

Gnomad4 AFR AF: 0.0464

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.0104

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.224

Alfa AF: 0.183 Hom.: 624

Bravo AF: 0.190

Asia WGS AF: 0.163 AC: 569 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.1053+13G>C in intron 11 of CLCNKB: This variant is not expected to have clinic al significance because it is not located within the splice consensus sequence a nd has been identified in 37.07% (4277/11538) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs35480349) . -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35480349; hg19: chr1-16377108; COSMIC: COSV65162263; COSMIC: COSV65162263;