NM_000085.5:c.1308C>T

Variant names:

• chr1-16051720-C-T
• rs5252
• NM_000085.5:c.1308C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000085.5(CLCNKB):​c.1308C>T​(p.Ile436Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,612,096 control chromosomes in the GnomAD database, including 11,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1699 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10078 hom.)
• Consequence: CLCNKB NM_000085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.36
• Publications: 13 publications found

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]

CLCNKB Gene-Disease associations (from GenCC):

• Bartter disease type 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Bartter disease type 4B

  Inheritance: AR Classification: STRONG Submitted by: G2P
• Bartter syndrome type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Gitelman syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-16051720-C-T is Benign according to our data. Variant chr1-16051720-C-T is described in ClinVar as Benign. ClinVar VariationId is 585700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.1308C>T	p.Ile436Ile	synonymous	Exon 14 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.801C>T	p.Ile267Ile	synonymous	Exon 7 of 13	NP_001159417.2	P51801-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.1308C>T	p.Ile436Ile	synonymous	Exon 14 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.1362C>T	p.Ile454Ile	synonymous	Exon 15 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1362C>T	p.Ile454Ile	synonymous	Exon 15 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20093 AN: 151888 Hom.: 1683 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0749

Gnomad ASJ AF: 0.0565

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

GnomAD2 exomes AF: 0.0961 AC: 24121 AN: 251022 AF XY: 0.0936

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.0106

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.0967

GnomAD4 exome AF: 0.111 AC: 162677 AN: 1460090 Hom.: 10078 Cov.: 33 AF XY: 0.109 AC XY: 79090 AN XY: 726456

African (AFR) AF: 0.220 AC: 7344 AN: 33424

American (AMR) AF: 0.0522 AC: 2334 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 1388 AN: 26124

East Asian (EAS) AF: 0.0139 AC: 550 AN: 39700

South Asian (SAS) AF: 0.0488 AC: 4204 AN: 86230

European-Finnish (FIN) AF: 0.126 AC: 6743 AN: 53332

Middle Eastern (MID) AF: 0.0743 AC: 427 AN: 5750

European-Non Finnish (NFE) AF: 0.120 AC: 133293 AN: 1110474

Other (OTH) AF: 0.106 AC: 6394 AN: 60334

GnomAD4 genome AF: 0.133 AC: 20150 AN: 152006 Hom.: 1699 Cov.: 32 AF XY: 0.128 AC XY: 9546 AN XY: 74306

African (AFR) AF: 0.217 AC: 8969 AN: 41418

American (AMR) AF: 0.0748 AC: 1143 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3466

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5170

South Asian (SAS) AF: 0.0440 AC: 212 AN: 4816

European-Finnish (FIN) AF: 0.121 AC: 1280 AN: 10592

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7958 AN: 67942

Other (OTH) AF: 0.117 AC: 246 AN: 2110

Alfa AF: 0.120 Hom.: 4839

Bravo AF: 0.132

Asia WGS AF: 0.0540 AC: 190 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.6
DANN	Benign	0.77
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs5252; hg19: chr1-16378215;