rs121909132

Variant names:

• chr1-16048537-G-A
• rs121909132
• NM_000085.5:c.610G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PP3_Strong PP5_Very_Strong

The NM_000085.5(CLCNKB):​c.610G>A​(p.Ala204Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,613,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV006581930: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:31803959)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A204V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 6.30
• Publications: 16 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV006581930: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 31803959).; SCV001816869: Published functional studies suggest a damaging effect due to altered gating properties resulting from decreased sensitivity to extracellular pH and Ca2+ (Bignon et al., 2020); SCV003523168: Experimental studies have shown that this missense change affects CLCNKB function (PMID: 31803959).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-16048537-G-A is Pathogenic according to our data. Variant chr1-16048537-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.610G>A	p.Ala204Thr	missense	Exon 7 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.-435G>A		upstream_gene	N/A	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.610G>A	p.Ala204Thr	missense	Exon 7 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.664G>A	p.Ala222Thr	missense	Exon 8 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.664G>A	p.Ala222Thr	missense	Exon 8 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000762 AC: 19 AN: 249318 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1460978 Hom.: 0 Cov.: 64 AF XY: 0.0000303 AC XY: 22 AN XY: 726750

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.000515 AC: 23 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111642

Other (OTH) AF: 0.0000497 AC: 3 AN: 60318

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74446

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000742 AC: 9

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Bartter disease type 3 (4)
3	-	-	not provided (3)
1	-	-	Bartter disease type 3;C4310805:Bartter disease type 4B (1)
1	-	-	Bartter syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.3
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.89
MutPred		0.89		Gain of glycosylation at A204 (P = 0.0578)
MVP		0.97
MPC		2.3
ClinPred		0.45	T
GERP RS		4.7
PromoterAI		-0.022	Neutral
Varity_R		0.46
gMVP		0.48
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121909132; hg19: chr1-16375032; COSMIC: COSV65161552; COSMIC: COSV65161552;