rs5253

chr1-16053701-T-C

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.1685T>C(p.Met562Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.96 in 1,613,870 control chromosomes in the GnomAD database, including 747,019 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61143 hom., cov: 32)
  • Exomes 𝑓: 0.97 (685876 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.34

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=8.2137257E-7).
• BP6: Variant 1-16053701-T-C is Benign according to our data. Variant chr1-16053701-T-C is described in ClinVar as [Benign]. Clinvar id is 447094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16053701-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.1685T>C	p.Met562Thr	missense_variant	16/20	ENST00000375679.9
CLCNKB	NM_001165945.2	c.1178T>C	p.Met393Thr	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1685T>C	p.Met562Thr	missense_variant	16/20	1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.888 AC: 134991 AN: 152028 Hom.: 61122 Cov.: 32

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.947

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.911

GnomAD3 exomes AF: 0.935 AC: 234686 AN: 251092 Hom.: 110523 AF XY: 0.941 AC XY: 127782 AN XY: 135846

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.948

Gnomad ASJ exome AF: 0.952

Gnomad EAS exome AF: 0.808

Gnomad SAS exome AF: 0.932

Gnomad FIN exome AF: 0.938

Gnomad NFE exome AF: 0.984

Gnomad OTH exome AF: 0.953

GnomAD4 exome AF: 0.967 AC: 1413473 AN: 1461724 Hom.: 685876 Cov.: 69 AF XY: 0.967 AC XY: 703266 AN XY: 727186

Gnomad4 AFR exome AF: 0.679

Gnomad4 AMR exome AF: 0.943

Gnomad4 ASJ exome AF: 0.953

Gnomad4 EAS exome AF: 0.818

Gnomad4 SAS exome AF: 0.932

Gnomad4 FIN exome AF: 0.936

Gnomad4 NFE exome AF: 0.988

Gnomad4 OTH exome AF: 0.945

GnomAD4 genome AF: 0.888 AC: 135058 AN: 152146 Hom.: 61143 Cov.: 32 AF XY: 0.885 AC XY: 65849 AN XY: 74384

Gnomad4 AFR AF: 0.696

Gnomad4 AMR AF: 0.928

Gnomad4 ASJ AF: 0.947

Gnomad4 EAS AF: 0.820

Gnomad4 SAS AF: 0.919

Gnomad4 FIN AF: 0.939

Gnomad4 NFE AF: 0.985

Gnomad4 OTH AF: 0.910

Alfa AF: 0.958 Hom.: 62547

Bravo AF: 0.877

TwinsUK AF: 0.989 AC: 3668

ALSPAC AF: 0.988 AC: 3809

ESP6500AA AF: 0.701 AC: 3087

ESP6500EA AF: 0.984 AC: 8462

ExAC AF: 0.931 AC: 112995

Asia WGS AF: 0.817 AC: 2840 AN: 3478

EpiCase AF: 0.984

EpiControl AF: 0.986

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Athena Diagnostics	Jul 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Met562Thr in exon 16 of CLCNKB: This variant is not expected to have clinical significance because it has been identified in 98.02% (65150/66466) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs5253). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	0.017
Dann	Benign	0.53
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.015	T;T;T
MetaRNN	Benign	8.2e-7	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.94	N;.;.
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	0.22	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.87	T;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.016
MPC		0.15
ClinPred		0.0096	T
GERP RS		-3.7
Varity_R		0.049
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs5253; hg19: chr1-16380196;