chr1-16052244-G-A

Variant names:

• chr1-16052244-G-A
• rs34652156
• NM_000085.5:c.1455G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000085.5(CLCNKB):​c.1455G>A​(p.Ala485Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,613,216 control chromosomes in the GnomAD database, including 899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (145 hom., cov: 33)
  • Exomes 𝑓: 0.028 (754 hom.)
• Consequence: CLCNKB NM_000085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.46
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-16052244-G-A is Benign according to our data. Variant chr1-16052244-G-A is described in ClinVar as Benign. ClinVar VariationId is 585703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 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.1455G>A	p.Ala485Ala	synonymous	Exon 15 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.948G>A	p.Ala316Ala	synonymous	Exon 8 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.1455G>A	p.Ala485Ala	synonymous	Exon 15 of 20	ENSP00000364831.5
	CLCNKB	ENST00000906263.1		c.1509G>A	p.Ala503Ala	synonymous	Exon 16 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1509G>A	p.Ala503Ala	synonymous	Exon 16 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5564 AN: 152182 Hom.: 145 Cov.: 33

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0271 AC: 6794 AN: 250566 AF XY: 0.0274

Gnomad AFR exome AF: 0.0580

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0489

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0370

Gnomad NFE exome AF: 0.0274

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0285 AC: 41633 AN: 1460916 Hom.: 754 Cov.: 37 AF XY: 0.0285 AC XY: 20697 AN XY: 726768

African (AFR) AF: 0.0577 AC: 1930 AN: 33474

American (AMR) AF: 0.0129 AC: 578 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0502 AC: 1311 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0283 AC: 2437 AN: 86246

European-Finnish (FIN) AF: 0.0356 AC: 1872 AN: 52524

Middle Eastern (MID) AF: 0.0482 AC: 277 AN: 5750

European-Non Finnish (NFE) AF: 0.0283 AC: 31523 AN: 1111986

Other (OTH) AF: 0.0282 AC: 1702 AN: 60378

GnomAD4 genome AF: 0.0366 AC: 5568 AN: 152300 Hom.: 145 Cov.: 33 AF XY: 0.0375 AC XY: 2796 AN XY: 74480

African (AFR) AF: 0.0587 AC: 2441 AN: 41550

American (AMR) AF: 0.0213 AC: 326 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0211 AC: 102 AN: 4828

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0287 AC: 1951 AN: 68016

Other (OTH) AF: 0.0302 AC: 64 AN: 2116

Alfa AF: 0.0274 Hom.: 42

Bravo AF: 0.0367

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0293

EpiControl AF: 0.0280

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.16
DANN	Benign	0.48
PhyloP100		-4.5
PromoterAI		-0.0068	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34652156; hg19: chr1-16378739; COSMIC: COSV65160149; COSMIC: COSV65160149;