rs945394

Variant names:

• chr1-16044404-G-A
• rs945394
• NM_000085.5:c.-7-82G>A

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.-7-82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,021,462 control chromosomes in the GnomAD database, including 190,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22489 hom., cov: 31)
  • Exomes 𝑓: 0.61 (168018 hom.)
• Consequence: CLCNKB NM_000085.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.9).
• BP6: Variant 1-16044404-G-A is Benign according to our data. Variant chr1-16044404-G-A is described in ClinVar as Benign. ClinVar VariationId is 1277450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.-7-82G>A		intron	N/A	NP_000076.2	P51801-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.-7-82G>A		intron	N/A	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906274.1		c.-89G>A		5_prime_UTR	Exon 1 of 19	ENSP00000576333.1
	CLCNKB	ENST00000906263.1		c.-7-82G>A		intron	N/A	ENSP00000576322.1

Frequencies

GnomAD3 genomes AF: 0.534 AC: 78846 AN: 147694 Hom.: 22476 Cov.: 31

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.672

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.647

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.577

GnomAD4 exome AF: 0.614 AC: 536826 AN: 873656 Hom.: 168018 AF XY: 0.618 AC XY: 278801 AN XY: 451276

African (AFR) AF: 0.251 AC: 5482 AN: 21844

American (AMR) AF: 0.705 AC: 24617 AN: 34940

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 13516 AN: 21858

East Asian (EAS) AF: 0.730 AC: 24360 AN: 33386

South Asian (SAS) AF: 0.659 AC: 45438 AN: 68944

European-Finnish (FIN) AF: 0.538 AC: 25258 AN: 46924

Middle Eastern (MID) AF: 0.634 AC: 2134 AN: 3364

European-Non Finnish (NFE) AF: 0.617 AC: 371590 AN: 601770

Other (OTH) AF: 0.601 AC: 24431 AN: 40626

GnomAD4 genome AF: 0.534 AC: 78877 AN: 147806 Hom.: 22489 Cov.: 31 AF XY: 0.537 AC XY: 38679 AN XY: 72068

African (AFR) AF: 0.277 AC: 10883 AN: 39356

American (AMR) AF: 0.659 AC: 9900 AN: 15030

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2104 AN: 3442

East Asian (EAS) AF: 0.712 AC: 3607 AN: 5068

South Asian (SAS) AF: 0.672 AC: 3198 AN: 4760

European-Finnish (FIN) AF: 0.554 AC: 5566 AN: 10046

Middle Eastern (MID) AF: 0.641 AC: 186 AN: 290

European-Non Finnish (NFE) AF: 0.623 AC: 41669 AN: 66862

Other (OTH) AF: 0.579 AC: 1190 AN: 2054

Alfa AF: 0.559 Hom.: 3174

Bravo AF: 0.518

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.64
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs945394; hg19: chr1-16370899; COSMIC: COSV65160124; COSMIC: COSV65160124;