1-16049696-C-T

Variant names:

• chr1-16049696-C-T
• rs7367494
• NM_000085.5:c.860C>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.860C>T​(p.Ala287Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.835 in 150,922 control chromosomes in the GnomAD database, including 54,696 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A287M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.83 (54696 hom., cov: 26)
  • Exomes 𝑓: 0.93 (635261 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.104
• Publications: 17 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=9.2536123E-7).
• BP6: Variant 1-16049696-C-T is Benign according to our data. Variant chr1-16049696-C-T is described in ClinVar as Benign. ClinVar VariationId is 447108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.860C>T	p.Ala287Val	missense	Exon 9 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.353C>T	p.Ala118Val	missense	Exon 2 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.860C>T	p.Ala287Val	missense	Exon 9 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.914C>T	p.Ala305Val	missense	Exon 10 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.914C>T	p.Ala305Val	missense	Exon 10 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.835 AC: 125886 AN: 150804 Hom.: 54670 Cov.: 26

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.907

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.936

Gnomad FIN AF: 0.923

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.856

GnomAD2 exomes AF: 0.925 AC: 222892 AN: 241002 AF XY: 0.929

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.960

Gnomad ASJ exome AF: 0.899

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.932

Gnomad NFE exome AF: 0.948

Gnomad OTH exome AF: 0.929

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.931 AC: 1357536 AN: 1457498 Hom.: 635261 Cov.: 40 AF XY: 0.932 AC XY: 676035 AN XY: 725266

African (AFR) AF: 0.546 AC: 18182 AN: 33280

American (AMR) AF: 0.942 AC: 41990 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 23120 AN: 26094

East Asian (EAS) AF: 0.999 AC: 39637 AN: 39672

South Asian (SAS) AF: 0.925 AC: 79750 AN: 86176

European-Finnish (FIN) AF: 0.923 AC: 49289 AN: 53406

Middle Eastern (MID) AF: 0.877 AC: 4982 AN: 5680

European-Non Finnish (NFE) AF: 0.943 AC: 1045651 AN: 1108372

Other (OTH) AF: 0.912 AC: 54935 AN: 60220

GnomAD4 genome AF: 0.835 AC: 125959 AN: 150922 Hom.: 54696 Cov.: 26 AF XY: 0.837 AC XY: 61653 AN XY: 73646

African (AFR) AF: 0.569 AC: 23282 AN: 40902

American (AMR) AF: 0.907 AC: 13793 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3057 AN: 3466

East Asian (EAS) AF: 0.998 AC: 5037 AN: 5048

South Asian (SAS) AF: 0.937 AC: 4449 AN: 4750

European-Finnish (FIN) AF: 0.923 AC: 9656 AN: 10460

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.941 AC: 63786 AN: 67776

Other (OTH) AF: 0.858 AC: 1808 AN: 2108

Alfa AF: 0.877 Hom.: 10283

Bravo AF: 0.820

ExAC AF: 0.909 AC: 110055

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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	0.061
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.093
DANN	Benign	0.21
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	9.3e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.35	N
PhyloP100		-0.10
PROVEAN	Benign	1.6	N
REVEL	Benign	0.22
Sift	Benign	0.84	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.054
MPC		1.2
ClinPred		0.0022	T
GERP RS		-6.5
Varity_R		0.031
gMVP		0.25
Mutation Taster		=97/3	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: rs7367494; hg19: chr1-16376191; COSMIC: COSV65159503; COSMIC: COSV65159503;