rs7367494

Positions:

• chr1-16049696-C-A
• chr1-16049696-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000085.5(CLCNKB):​c.860C>A​(p.Ala287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A287V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 26)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.860C>A	p.Ala287Glu	missense_variant	9/20	ENST00000375679.9
CLCNKB	NM_001165945.2	c.353C>A	p.Ala118Glu	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.860C>A	p.Ala287Glu	missense_variant	9/20	1	NM_000085.5	P4

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	11
DANN	Benign	0.92
DEOGEN2	Uncertain	0.76	D;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.51	T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.77	P;.
Vest4		0.58
MutPred		0.64		Loss of helix (P = 0.2022);.;
MVP		0.74
MPC		2.2
ClinPred		0.69	D
GERP RS		-6.5
Varity_R		0.68
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs7367494; hg19: chr1-16376191;