1-16053757-C-A

Variant names:

• chr1-16053757-C-A
• rs2275167
• NM_000085.5:c.1741C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000375679.9(CLCNKB):​c.1741C>A​(p.Leu581Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,452 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L581L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLCNKB ENST00000375679.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.515
• Publications: 19 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375679.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.1741C>A	p.Leu581Met	missense	Exon 16 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.1234C>A	p.Leu412Met	missense	Exon 9 of 13	NP_001159417.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.1741C>A	p.Leu581Met	missense	Exon 16 of 20	ENSP00000364831.5
	CLCNKB	ENST00000682338.1		c.1741C>A	p.Leu581Met	missense	Exon 18 of 22	ENSP00000507062.1
	CLCNKB	ENST00000682793.1		c.1741C>A	p.Leu581Met	missense	Exon 16 of 20	ENSP00000506910.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461452 Hom.: 0 Cov.: 72 AF XY: 0.00 AC XY: 0 AN XY: 727026

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 7419

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.047
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.52
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.39
MutPred		0.61		Gain of disorder (P = 0.0857)
MVP		0.88
MPC		0.56
ClinPred		0.90	D
GERP RS		1.6
Varity_R		0.26
gMVP		0.41
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2275167; hg19: chr1-16380252;