rs143663847

Variant names:

• chr1-16055706-G-A
• rs143663847
• NM_000085.5:c.1877G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-16055706-G-A
• chr1-16055706-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000085.5(CLCNKB):​c.1877G>A​(p.Cys626Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,758 control chromosomes in the GnomAD database, including 552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (69 hom., cov: 33)
  • Exomes 𝑓: 0.014 (483 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.98
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029669702).
• BP6: Variant 1-16055706-G-A is Benign according to our data. Variant chr1-16055706-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.072 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.1877G>A	p.Cys626Tyr	missense	Exon 18 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.1367G>A	p.Cys456Tyr	missense	Exon 11 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.1877G>A	p.Cys626Tyr	missense	Exon 18 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.1931G>A	p.Cys644Tyr	missense	Exon 19 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1928G>A	p.Cys643Tyr	missense	Exon 19 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2261 AN: 152178 Hom.: 69 Cov.: 33

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0751

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00753

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0257 AC: 6453 AN: 251146 AF XY: 0.0222

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00665

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0144 AC: 21026 AN: 1461462 Hom.: 483 Cov.: 32 AF XY: 0.0140 AC XY: 10207 AN XY: 727058

African (AFR) AF: 0.00164 AC: 55 AN: 33480

American (AMR) AF: 0.121 AC: 5428 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0160 AC: 1381 AN: 86252

European-Finnish (FIN) AF: 0.00764 AC: 406 AN: 53120

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12860 AN: 1111910

Other (OTH) AF: 0.0127 AC: 767 AN: 60386

GnomAD4 genome AF: 0.0149 AC: 2269 AN: 152296 Hom.: 69 Cov.: 33 AF XY: 0.0157 AC XY: 1169 AN XY: 74466

African (AFR) AF: 0.00354 AC: 147 AN: 41554

American (AMR) AF: 0.0756 AC: 1156 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4830

European-Finnish (FIN) AF: 0.00753 AC: 80 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 764 AN: 68034

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.0124 Hom.: 56

Bravo AF: 0.0217

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.0228 AC: 2767

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.0123

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0030	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.0
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.35
MPC		0.79
ClinPred		0.022	T
GERP RS		4.7
Varity_R		0.69
gMVP		0.44
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs143663847; hg19: chr1-16382201; COSMIC: COSV65154501; COSMIC: COSV65154501;