1-16055591-C-T

Variant names:

• chr1-16055591-C-T
• rs2297727
• NM_000085.5:c.1845+68C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000085.5(CLCNKB):​c.1845+68C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,570,726 control chromosomes in the GnomAD database, including 173,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14487 hom., cov: 31)
  • Exomes 𝑓: 0.47 (158844 hom.)
• Consequence: CLCNKB NM_000085.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-16055591-C-T is Benign according to our data. Variant chr1-16055591-C-T is described in ClinVar as Benign. ClinVar VariationId is 1229089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5	c.1845+68C>T		intron_variant	Intron 17 of 19	ENST00000375679.9	NP_000076.2
CLCNKB	NM_001165945.2	c.1338+68C>T		intron_variant	Intron 10 of 12		NP_001159417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1845+68C>T		intron_variant	Intron 17 of 19	1	NM_000085.5	ENSP00000364831.5

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64478 AN: 151508 Hom.: 14479 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.437

GnomAD4 exome AF: 0.468 AC: 664408 AN: 1419100 Hom.: 158844 Cov.: 25 AF XY: 0.468 AC XY: 331124 AN XY: 707604

African (AFR) AF: 0.280 AC: 9170 AN: 32734

American (AMR) AF: 0.414 AC: 18199 AN: 44006

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 10452 AN: 25756

East Asian (EAS) AF: 0.820 AC: 32314 AN: 39402

South Asian (SAS) AF: 0.430 AC: 36467 AN: 84840

European-Finnish (FIN) AF: 0.487 AC: 25296 AN: 51986

Middle Eastern (MID) AF: 0.396 AC: 2240 AN: 5656

European-Non Finnish (NFE) AF: 0.467 AC: 502768 AN: 1075744

Other (OTH) AF: 0.466 AC: 27502 AN: 58976

GnomAD4 genome AF: 0.425 AC: 64505 AN: 151626 Hom.: 14487 Cov.: 31 AF XY: 0.428 AC XY: 31740 AN XY: 74088

African (AFR) AF: 0.298 AC: 12302 AN: 41292

American (AMR) AF: 0.420 AC: 6413 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1352 AN: 3464

East Asian (EAS) AF: 0.805 AC: 4135 AN: 5136

South Asian (SAS) AF: 0.442 AC: 2123 AN: 4804

European-Finnish (FIN) AF: 0.491 AC: 5159 AN: 10508

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.467 AC: 31710 AN: 67842

Other (OTH) AF: 0.435 AC: 920 AN: 2114

Alfa AF: 0.440 Hom.: 1921

Bravo AF: 0.413

Asia WGS AF: 0.548 AC: 1904 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.19
DANN	Benign	0.40
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2297727; hg19: chr1-16382086;