rs6650118

Variant names:

• chr1-16051504-C-T
• rs6650118
• NM_000085.5:c.1254C>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.1254C>T​(p.Thr418Thr) 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 1,610,352 control chromosomes in the GnomAD database, including 11,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1679 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10057 hom.)
• Consequence: CLCNKB NM_000085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.62
• Publications: 5 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=-0.7).
• BP6: Variant 1-16051504-C-T is Benign according to our data. Variant chr1-16051504-C-T is described in ClinVar as Benign. ClinVar VariationId is 585698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.62 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.1254C>T	p.Thr418Thr	synonymous	Exon 13 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.747C>T	p.Thr249Thr	synonymous	Exon 6 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.1254C>T	p.Thr418Thr	synonymous	Exon 13 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.1308C>T	p.Thr436Thr	synonymous	Exon 14 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1308C>T	p.Thr436Thr	synonymous	Exon 14 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20088 AN: 152014 Hom.: 1663 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0749

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.0961 AC: 24157 AN: 251452 AF XY: 0.0935

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0507

Gnomad EAS exome AF: 0.0105

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.111 AC: 161443 AN: 1458220 Hom.: 10057 Cov.: 34 AF XY: 0.108 AC XY: 78524 AN XY: 725614

African (AFR) AF: 0.220 AC: 7334 AN: 33356

American (AMR) AF: 0.0522 AC: 2333 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 1386 AN: 26120

East Asian (EAS) AF: 0.0137 AC: 545 AN: 39700

South Asian (SAS) AF: 0.0488 AC: 4206 AN: 86230

European-Finnish (FIN) AF: 0.126 AC: 6749 AN: 53406

Middle Eastern (MID) AF: 0.0738 AC: 425 AN: 5760

European-Non Finnish (NFE) AF: 0.119 AC: 132100 AN: 1108640

Other (OTH) AF: 0.106 AC: 6365 AN: 60288

GnomAD4 genome AF: 0.132 AC: 20145 AN: 152132 Hom.: 1679 Cov.: 32 AF XY: 0.128 AC XY: 9550 AN XY: 74370

African (AFR) AF: 0.217 AC: 8985 AN: 41472

American (AMR) AF: 0.0748 AC: 1144 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0567 AC: 197 AN: 3472

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5176

South Asian (SAS) AF: 0.0442 AC: 213 AN: 4822

European-Finnish (FIN) AF: 0.120 AC: 1274 AN: 10596

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

European-Non Finnish (NFE) AF: 0.117 AC: 7939 AN: 67978

Other (OTH) AF: 0.117 AC: 247 AN: 2112

Alfa AF: 0.0795 Hom.: 549

Bravo AF: 0.132

Asia WGS AF: 0.0540 AC: 189 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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.084
DANN	Benign	0.35
PhyloP100		-3.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6650118; hg19: chr1-16377999;