rs2015352

chr1-16044572-G-Achr1-16044572-G-Cchr1-16044572-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000085.5(CLCNKB):c.80G>A(p.Arg27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000461 in 151,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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. R27L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00800

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11572239).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.80G>A	p.Arg27His	missense_variant	2/20	ENST00000375679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.80G>A	p.Arg27His	missense_variant	2/20	1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151780 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000132 AC: 3 AN: 226810 Hom.: 0 AF XY: 0.00000818 AC XY: 1 AN XY: 122216

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000593

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000981

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000269 AC: 39 AN: 1449300 Hom.: 0 Cov.: 48 AF XY: 0.0000250 AC XY: 18 AN XY: 719472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000289

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151898 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74224

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.13	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	0.95	N
Sift4G	Benign	0.073	T;T
Polyphen		0.014	.;B
Vest4		0.18
MVP		0.87
MPC		0.036
ClinPred		0.046	T
GERP RS		3.2
Varity_R		0.050
gMVP		0.40

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: rs2015352; hg19: chr1-16371067;