1-16053748-A-G

Variant names:

• chr1-16053748-A-G
• rs2275166
• NM_000085.5:c.1732A>G

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.1732A>G​(p.Lys578Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,610,920 control chromosomes in the GnomAD database, including 363,773 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (37137 hom., cov: 32)
  • Exomes 𝑓: 0.67 (326636 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.01
• Publications: 31 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 (MetaRNN=5.6256567E-6).
• BP6: Variant 1-16053748-A-G is Benign according to our data. Variant chr1-16053748-A-G is described in ClinVar as Benign. ClinVar VariationId is 447096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 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.1732A>G	p.Lys578Glu	missense	Exon 16 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.1225A>G	p.Lys409Glu	missense	Exon 9 of 13	NP_001159417.2	P51801-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.1732A>G	p.Lys578Glu	missense	Exon 16 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.1786A>G	p.Lys596Glu	missense	Exon 17 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1786A>G	p.Lys596Glu	missense	Exon 17 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105369 AN: 151652 Hom.: 37116 Cov.: 32

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.668

GnomAD2 exomes AF: 0.653 AC: 163268 AN: 250048 AF XY: 0.650

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.582

Gnomad EAS exome AF: 0.795

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.667 AC: 973531 AN: 1459150 Hom.: 326636 Cov.: 72 AF XY: 0.664 AC XY: 482151 AN XY: 725916

African (AFR) AF: 0.807 AC: 27025 AN: 33468

American (AMR) AF: 0.524 AC: 23423 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 15366 AN: 26100

East Asian (EAS) AF: 0.811 AC: 32172 AN: 39690

South Asian (SAS) AF: 0.583 AC: 50209 AN: 86170

European-Finnish (FIN) AF: 0.737 AC: 39134 AN: 53124

Middle Eastern (MID) AF: 0.590 AC: 3399 AN: 5762

European-Non Finnish (NFE) AF: 0.669 AC: 742546 AN: 1109832

Other (OTH) AF: 0.667 AC: 40257 AN: 60318

GnomAD4 genome AF: 0.695 AC: 105426 AN: 151770 Hom.: 37137 Cov.: 32 AF XY: 0.693 AC XY: 51385 AN XY: 74168

African (AFR) AF: 0.798 AC: 33056 AN: 41414

American (AMR) AF: 0.576 AC: 8783 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 2015 AN: 3468

East Asian (EAS) AF: 0.806 AC: 4154 AN: 5154

South Asian (SAS) AF: 0.582 AC: 2794 AN: 4802

European-Finnish (FIN) AF: 0.739 AC: 7771 AN: 10522

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.661 AC: 44851 AN: 67848

Other (OTH) AF: 0.665 AC: 1401 AN: 2108

Alfa AF: 0.663 Hom.: 31524

Bravo AF: 0.688

TwinsUK AF: 0.680 AC: 2521

ALSPAC AF: 0.682 AC: 2629

ESP6500AA AF: 0.799 AC: 3522

ESP6500EA AF: 0.650 AC: 5593

ExAC AF: 0.658 AC: 79931

EpiCase AF: 0.648

EpiControl AF: 0.645

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Bartter disease type 3 (1)
-	-	1	Bartter disease type 4B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.1
DANN	Benign	0.77
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.0087	T
MetaRNN	Benign	0.0000056	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.6	N
PhyloP100		1.0
PROVEAN	Benign	1.1	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.032
MPC		0.19
ClinPred		0.0013	T
GERP RS		1.4
Varity_R		0.090
gMVP		0.42
Mutation Taster		=97/3	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: rs2275166; hg19: chr1-16380243; COSMIC: COSV107483760; COSMIC: COSV107483760;