rs11588392

Positions:

• chr1-16049015-G-A

Variant summary

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

The NM_001165945.2(CLCNKB):​c.44G>A​(p.Gly15Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,604,684 control chromosomes in the GnomAD database, including 3,984 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (1345 hom., cov: 34)
  • Exomes 𝑓: 0.049 (2639 hom.)
• Consequence: CLCNKB NM_001165945.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.259

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005407542).
• BP6: Variant 1-16049015-G-A is Benign according to our data. Variant chr1-16049015-G-A is described in ClinVar as [Benign]. Clinvar id is 504913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5	c.656-105G>A		intron_variant		ENST00000375679.9	NP_000076.2
CLCNKB	NM_001165945.2	c.44G>A	p.Gly15Glu	missense_variant	1/13		NP_001159417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9	c.656-105G>A		intron_variant		1	NM_000085.5	ENSP00000364831.5

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15020 AN: 152040 Hom.: 1343 Cov.: 34

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0833

GnomAD3 exomes AF: 0.0531 AC: 13017 AN: 245060 Hom.: 686 AF XY: 0.0499 AC XY: 6643 AN XY: 133142

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0917

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0257

Gnomad FIN exome AF: 0.0719

Gnomad NFE exome AF: 0.0422

Gnomad OTH exome AF: 0.0558

GnomAD4 exome AF: 0.0488 AC: 70823 AN: 1452526 Hom.: 2639 Cov.: 54 AF XY: 0.0476 AC XY: 34375 AN XY: 721706

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.0378

Gnomad4 ASJ exome AF: 0.0977

Gnomad4 EAS exome AF: 0.000329

Gnomad4 SAS exome AF: 0.0259

Gnomad4 FIN exome AF: 0.0718

Gnomad4 NFE exome AF: 0.0439

Gnomad4 OTH exome AF: 0.0601

GnomAD4 genome AF: 0.0988 AC: 15036 AN: 152158 Hom.: 1345 Cov.: 34 AF XY: 0.0972 AC XY: 7228 AN XY: 74392

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.0622

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0219

Gnomad4 FIN AF: 0.0712

Gnomad4 NFE AF: 0.0434

Gnomad4 OTH AF: 0.0824

Alfa AF: 0.0619 Hom.: 418

Bravo AF: 0.105

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0522 AC: 201

ESP6500AA AF: 0.214 AC: 296

ESP6500EA AF: 0.0469 AC: 149

ExAC AF: 0.0545 AC: 6615

Asia WGS AF: 0.0230 AC: 83 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 21, 2016

p.Gly15Glu in exon 1 of CLCNKB: This variant is not expected to have clinical si gnificance because it has been identified in 26.32% (2312/8784) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs11588392). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.3
DANN	Benign	0.93
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.044
ClinPred		0.012	T
GERP RS		-4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11588392; hg19: chr1-16375510;