1-16052230-A-T

Position:

• chr1-16052230-A-T

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.1441A>T​(p.Thr481Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,612,846 control chromosomes in the GnomAD database, including 11,747 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1691 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10056 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.954

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=0.0018473566).
• BP6: Variant 1-16052230-A-T is Benign according to our data. Variant chr1-16052230-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 585702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16052230-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5	c.1441A>T	p.Thr481Ser	missense_variant	15/20	ENST00000375679.9	NP_000076.2
CLCNKB	NM_001165945.2	c.934A>T	p.Thr312Ser	missense_variant	8/13		NP_001159417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1441A>T	p.Thr481Ser	missense_variant	15/20	1	NM_000085.5	ENSP00000364831	P4

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20103 AN: 152102 Hom.: 1675 Cov.: 33

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0752

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.0442

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.0956 AC: 23916 AN: 250126 Hom.: 1518 AF XY: 0.0932 AC XY: 12636 AN XY: 135508

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0480

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.0488

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0964

GnomAD4 exome AF: 0.112 AC: 163065 AN: 1460626 Hom.: 10056 Cov.: 36 AF XY: 0.109 AC XY: 79213 AN XY: 726596

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.0522

Gnomad4 ASJ exome AF: 0.0533

Gnomad4 EAS exome AF: 0.0137

Gnomad4 SAS exome AF: 0.0488

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.132 AC: 20160 AN: 152220 Hom.: 1691 Cov.: 33 AF XY: 0.129 AC XY: 9569 AN XY: 74434

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.0751

Gnomad4 ASJ AF: 0.0568

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0440

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.117

Alfa AF: 0.116 Hom.: 362

Bravo AF: 0.131

TwinsUK AF: 0.126 AC: 466

ALSPAC AF: 0.129 AC: 496

ESP6500AA AF: 0.211 AC: 928

ESP6500EA AF: 0.110 AC: 942

ExAC AF: 0.101 AC: 12272

Asia WGS AF: 0.0550 AC: 191 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	This variant is associated with the following publications: (PMID: 15148291, 14675050, 19226700) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.87
DEOGEN2	Uncertain	0.61	.;D;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.64	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.91	.;L;.
MutationTaster	Benign	0.44	P;P
PROVEAN	Uncertain	-2.6	.;D;D
REVEL	Benign	0.24
Sift	Benign	0.27	.;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.058	.;B;.
Vest4		0.22
MutPred		0.27		.;Loss of helix (P = 0.0196);.;
MPC		0.18
ClinPred		0.031	T
GERP RS		-3.3
Varity_R		0.16
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12140311; hg19: chr1-16378725;