rs115910575

chr1-16052192-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000085.5(CLCNKB):c.1409-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,612,826 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (5 hom.)
• Consequence: CLCNKB NM_000085.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009232
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00400

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-16052192-T-C is Benign according to our data. Variant chr1-16052192-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 447091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00289 (440/152368) while in subpopulation AFR AF= 0.00959 (399/41588). AF 95% confidence interval is 0.00882. There are 3 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.1409-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000375679.9
CLCNKB	NM_001165945.2	c.902-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1409-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152250 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00960

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.000771 AC: 192 AN: 248930 Hom.: 0 AF XY: 0.000503 AC XY: 68 AN XY: 135056

Gnomad AFR exome AF: 0.00903

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000538

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000353 AC: 515 AN: 1460458 Hom.: 5 Cov.: 33 AF XY: 0.000296 AC XY: 215 AN XY: 726574

Gnomad4 AFR exome AF: 0.00986

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000675

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152368 Hom.: 3 Cov.: 33 AF XY: 0.00260 AC XY: 194 AN XY: 74522

Gnomad4 AFR AF: 0.00959

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00158 Hom.: 0

Bravo AF: 0.00336

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 10, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	3.0
Dann	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.018
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: rs115910575; hg19: chr1-16378687;