rs1889790

chr1-16048569-A-Cchr1-16048569-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000085.5(CLCNKB):c.642A>C(p.Ala214=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 151,746 control chromosomes in the GnomAD database, including 53,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53688 hom., cov: 31)
  • Exomes 𝑓: 0.92 (614566 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.93

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-16048569-A-C is Benign according to our data. Variant chr1-16048569-A-C is described in ClinVar as [Benign]. Clinvar id is 504915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16048569-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.93 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.642A>C	p.Ala214=	synonymous_variant	7/20	ENST00000375679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.642A>C	p.Ala214=	synonymous_variant	7/20	1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125196 AN: 151630 Hom.: 53659 Cov.: 31

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.896

Gnomad ASJ AF: 0.880

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.936

Gnomad FIN AF: 0.918

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.848

GnomAD3 exomes AF: 0.907 AC: 227189 AN: 250522 Hom.: 104224 AF XY: 0.912 AC XY: 123627 AN XY: 135526

Gnomad AFR exome AF: 0.559

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.890

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.926

Gnomad FIN exome AF: 0.919

Gnomad NFE exome AF: 0.926

Gnomad OTH exome AF: 0.906

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.915 AC: 1337179 AN: 1461102 Hom.: 614566 Cov.: 63 AF XY: 0.917 AC XY: 666207 AN XY: 726852

Gnomad4 AFR exome AF: 0.549

Gnomad4 AMR exome AF: 0.932

Gnomad4 ASJ exome AF: 0.884

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.924

Gnomad4 FIN exome AF: 0.918

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.899

GnomAD4 genome AF: 0.826 AC: 125274 AN: 151746 Hom.: 53688 Cov.: 31 AF XY: 0.829 AC XY: 61457 AN XY: 74172

Gnomad4 AFR AF: 0.571

Gnomad4 AMR AF: 0.896

Gnomad4 ASJ AF: 0.880

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.936

Gnomad4 FIN AF: 0.918

Gnomad4 NFE AF: 0.924

Gnomad4 OTH AF: 0.850

Alfa AF: 0.874 Hom.: 21208

Bravo AF: 0.810

Asia WGS AF: 0.948 AC: 3294 AN: 3478

EpiCase AF: 0.917

EpiControl AF: 0.922

ClinVar

Significance: Benign

Submissions summary: Benign:6

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.Ala214Ala in exon 7 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 99.93% (8628/8634) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs1889790). -
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	-	- -

Bartter disease type 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

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	-0.83
Cadd	Benign	0.64
Dann	Benign	0.70

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: rs1889790; hg19: chr1-16375064; COSMIC: COSV65161020; COSMIC: COSV65161020;