rs2275167

Positions:

• chr1-16053757-C-A
• chr1-16053757-C-G
• chr1-16053757-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000085.5(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 NM_000085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.515

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.1741C>A	p.Leu581Met	missense_variant	16/20	ENST00000375679.9
CLCNKB	NM_001165945.2	c.1234C>A	p.Leu412Met	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1741C>A	p.Leu581Met	missense_variant	16/20	1	NM_000085.5	P4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	0.89	D;D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.025	D;D;D
Sift4G	Uncertain	0.014	D;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2275167; hg19: chr1-16380252;