rs144517772

Variant names:

• chr1-16049164-T-C
• rs144517772
• NM_000085.5:c.700T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000085.5(CLCNKB):​c.700T>C​(p.Trp234Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,613,402 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.26
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00786981).
• BP6: Variant 1-16049164-T-C is Benign according to our data. Variant chr1-16049164-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523320.

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.700T>C	p.Trp234Arg	missense	Exon 8 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.193T>C	p.Trp65Arg	missense	Exon 1 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.700T>C	p.Trp234Arg	missense	Exon 8 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.754T>C	p.Trp252Arg	missense	Exon 9 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.754T>C	p.Trp252Arg	missense	Exon 9 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152176 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000430 AC: 108 AN: 251436 AF XY: 0.000397

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000282 AC: 412 AN: 1461108 Hom.: 1 Cov.: 48 AF XY: 0.000292 AC XY: 212 AN XY: 726766

African (AFR) AF: 0.00149 AC: 50 AN: 33446

American (AMR) AF: 0.000447 AC: 20 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86216

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5210

European-Non Finnish (NFE) AF: 0.000255 AC: 283 AN: 1111970

Other (OTH) AF: 0.000216 AC: 13 AN: 60302

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152294 Hom.: 1 Cov.: 34 AF XY: 0.000752 AC XY: 56 AN XY: 74480

African (AFR) AF: 0.00221 AC: 92 AN: 41560

American (AMR) AF: 0.000980 AC: 15 AN: 15308

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

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000573 Hom.: 0

Bravo AF: 0.000884

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000511 AC: 62

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	-	Bartter disease type 3 (1)
-	1	-	Hematuria;C0033687:Proteinuria (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.77	N
PhyloP100		1.3
PROVEAN	Benign	2.8	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.55		Gain of catalytic residue at W234 (P = 0.0566)
MVP		0.83
MPC		1.9
ClinPred		0.012	T
GERP RS		4.0
PromoterAI		0.011	Neutral
Varity_R		0.15
gMVP		0.50
Mutation Taster		=30/70	disease causing

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: rs144517772; hg19: chr1-16375659;