1-16053757-C-T

Variant names:

• chr1-16053757-C-T
• rs2275167
• NM_000085.5:c.1741C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000085.5(CLCNKB):​c.1741C>T​(p.Leu581Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 1,610,996 control chromosomes in the GnomAD database, including 333,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29525 hom., cov: 32)
  • Exomes 𝑓: 0.64 (304267 hom.)
• Consequence: CLCNKB NM_000085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.515
• Publications: 19 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 -16 ACMG points.

• BP6: Variant 1-16053757-C-T is Benign according to our data. Variant chr1-16053757-C-T is described in ClinVar as Benign. ClinVar VariationId is 447097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.779 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.1741C>T	p.Leu581Leu	synonymous	Exon 16 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.1234C>T	p.Leu412Leu	synonymous	Exon 9 of 13	NP_001159417.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.1741C>T	p.Leu581Leu	synonymous	Exon 16 of 20	ENSP00000364831.5
	CLCNKB	ENST00000906263.1		c.1795C>T	p.Leu599Leu	synonymous	Exon 17 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1795C>T	p.Leu599Leu	synonymous	Exon 17 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94109 AN: 151610 Hom.: 29518 Cov.: 32

Gnomad AFR AF: 0.585

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.605

GnomAD2 exomes AF: 0.618 AC: 154620 AN: 250188 AF XY: 0.618

Gnomad AFR exome AF: 0.577

Gnomad AMR exome AF: 0.493

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.789

Gnomad FIN exome AF: 0.718

Gnomad NFE exome AF: 0.644

Gnomad OTH exome AF: 0.629

GnomAD4 exome AF: 0.644 AC: 939123 AN: 1459268 Hom.: 304267 Cov.: 72 AF XY: 0.640 AC XY: 464968 AN XY: 725956

African (AFR) AF: 0.579 AC: 19361 AN: 33464

American (AMR) AF: 0.496 AC: 22145 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 14708 AN: 26100

East Asian (EAS) AF: 0.806 AC: 31984 AN: 39690

South Asian (SAS) AF: 0.532 AC: 45854 AN: 86182

European-Finnish (FIN) AF: 0.717 AC: 38097 AN: 53116

Middle Eastern (MID) AF: 0.569 AC: 3274 AN: 5758

European-Non Finnish (NFE) AF: 0.654 AC: 725360 AN: 1109960

Other (OTH) AF: 0.636 AC: 38340 AN: 60322

GnomAD4 genome AF: 0.620 AC: 94135 AN: 151728 Hom.: 29525 Cov.: 32 AF XY: 0.619 AC XY: 45920 AN XY: 74134

African (AFR) AF: 0.585 AC: 24210 AN: 41408

American (AMR) AF: 0.534 AC: 8144 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1907 AN: 3468

East Asian (EAS) AF: 0.799 AC: 4119 AN: 5152

South Asian (SAS) AF: 0.531 AC: 2553 AN: 4806

European-Finnish (FIN) AF: 0.719 AC: 7556 AN: 10504

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43787 AN: 67826

Other (OTH) AF: 0.601 AC: 1267 AN: 2108

Alfa AF: 0.604 Hom.: 7419

Bravo AF: 0.605

EpiCase AF: 0.633

EpiControl AF: 0.627

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Bartter disease type 3 (1)
-	-	1	Bartter disease type 4B (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2275167; hg19: chr1-16380252; COSMIC: COSV65152867; COSMIC: COSV65152867;