rs5257

Positions:

• chr1-16046629-A-G
• chr1-16046629-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000085.5(CLCNKB):​c.324A>G​(p.Ser108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,613,688 control chromosomes in the GnomAD database, including 520,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (40556 hom., cov: 32)
  • Exomes 𝑓: 0.81 (480017 hom.)
• Consequence: CLCNKB NM_000085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.89

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 -16 ACMG points.

• BP6: Variant 1-16046629-A-G is Benign according to our data. Variant chr1-16046629-A-G is described in ClinVar as [Benign]. Clinvar id is 447104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16046629-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.324A>G	p.Ser108=	synonymous_variant	4/20	ENST00000375679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.324A>G	p.Ser108=	synonymous_variant	4/20	1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106696 AN: 151836 Hom.: 40534 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.856

Gnomad AMR AF: 0.829

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.891

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.809

Gnomad OTH AF: 0.742

GnomAD3 exomes AF: 0.812 AC: 204128 AN: 251366 Hom.: 85128 AF XY: 0.819 AC XY: 111246 AN XY: 135872

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.899

Gnomad ASJ exome AF: 0.835

Gnomad EAS exome AF: 0.989

Gnomad SAS exome AF: 0.874

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.809

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.806 AC: 1178779 AN: 1461734 Hom.: 480017 Cov.: 58 AF XY: 0.810 AC XY: 588877 AN XY: 727184

Gnomad4 AFR exome AF: 0.366

Gnomad4 AMR exome AF: 0.889

Gnomad4 ASJ exome AF: 0.824

Gnomad4 EAS exome AF: 0.986

Gnomad4 SAS exome AF: 0.874

Gnomad4 FIN exome AF: 0.767

Gnomad4 NFE exome AF: 0.807

Gnomad4 OTH exome AF: 0.797

GnomAD4 genome AF: 0.702 AC: 106740 AN: 151954 Hom.: 40556 Cov.: 32 AF XY: 0.709 AC XY: 52631 AN XY: 74266

Gnomad4 AFR AF: 0.389

Gnomad4 AMR AF: 0.829

Gnomad4 ASJ AF: 0.815

Gnomad4 EAS AF: 0.988

Gnomad4 SAS AF: 0.892

Gnomad4 FIN AF: 0.773

Gnomad4 NFE AF: 0.809

Gnomad4 OTH AF: 0.745

Alfa AF: 0.793 Hom.: 88420

Bravo AF: 0.693

Asia WGS AF: 0.898 AC: 3121 AN: 3478

EpiCase AF: 0.815

EpiControl AF: 0.817

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ser108Ser in exon 4 of CLCNKB: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 98.98% (8566/8654) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs5257). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Bartter disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Bartter disease type 4B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.18
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5257; hg19: chr1-16373124;