1-16053748-A-G

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.1732A>G(p.Lys578Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,610,920 control chromosomes in the GnomAD database, including 363,773 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 0.69 (37137 hom., cov: 32)
  • Exomes 𝑓: 0.67 (326636 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.01

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=5.6256567E-6).
• BP6: Variant 1-16053748-A-G is Benign according to our data. Variant chr1-16053748-A-G is described in ClinVar as [Benign]. Clinvar id is 447096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16053748-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.1732A>G	p.Lys578Glu	missense_variant	16/20	ENST00000375679.9
CLCNKB	NM_001165945.2	c.1225A>G	p.Lys409Glu	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1732A>G	p.Lys578Glu	missense_variant	16/20	1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105369 AN: 151652 Hom.: 37116 Cov.: 32

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.668

GnomAD3 exomes AF: 0.653 AC: 163268 AN: 250048 Hom.: 54196 AF XY: 0.650 AC XY: 87976 AN XY: 135366

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.582

Gnomad EAS exome AF: 0.795

Gnomad SAS exome AF: 0.583

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.667 AC: 973531 AN: 1459150 Hom.: 326636 Cov.: 72 AF XY: 0.664 AC XY: 482151 AN XY: 725916

Gnomad4 AFR exome AF: 0.807

Gnomad4 AMR exome AF: 0.524

Gnomad4 ASJ exome AF: 0.589

Gnomad4 EAS exome AF: 0.811

Gnomad4 SAS exome AF: 0.583

Gnomad4 FIN exome AF: 0.737

Gnomad4 NFE exome AF: 0.669

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.695 AC: 105426 AN: 151770 Hom.: 37137 Cov.: 32 AF XY: 0.693 AC XY: 51385 AN XY: 74168

Gnomad4 AFR AF: 0.798

Gnomad4 AMR AF: 0.576

Gnomad4 ASJ AF: 0.581

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.582

Gnomad4 FIN AF: 0.739

Gnomad4 NFE AF: 0.661

Gnomad4 OTH AF: 0.665

Alfa AF: 0.665 Hom.: 17395

Bravo AF: 0.688

TwinsUK AF: 0.680 AC: 2521

ALSPAC AF: 0.682 AC: 2629

ESP6500AA AF: 0.799 AC: 3522

ESP6500EA AF: 0.650 AC: 5593

ExAC AF: 0.658 AC: 79931

EpiCase AF: 0.648

EpiControl AF: 0.645

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 26814133, 29105529) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Lys578Glu in exon 16 of CLCNKB: This variant is not expected to have clinical significance because it has been identified in 79.60% (8227/10336) of African ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs2275166). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2021	- -

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	0.051
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	4.1
Dann	Benign	0.77
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.0087	T;T;T
MetaRNN	Benign	0.0000056	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.6	N;.;.
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.032
MPC		0.19
ClinPred		0.0013	T
GERP RS		1.4
Varity_R		0.090
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2275166; hg19: chr1-16380243;