rs5253

Variant names:

• chr1-16053701-T-C
• rs5253
• NM_000085.5:c.1685T>C
• CLCNKB p.Met562Thr

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.1685T>C​(p.Met562Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.96 in 1,613,870 control chromosomes in the GnomAD database, including 747,019 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61143 hom., cov: 32)
  • Exomes 𝑓: 0.97 (685876 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.34
• Publications: 34 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=8.2137257E-7).
• BP6: Variant 1-16053701-T-C is Benign according to our data. Variant chr1-16053701-T-C is described in ClinVar as Benign. ClinVar VariationId is 447094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.979 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.1685T>C	p.Met562Thr	missense	Exon 16 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.1178T>C	p.Met393Thr	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.1685T>C	p.Met562Thr	missense	Exon 16 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.1739T>C	p.Met580Thr	missense	Exon 17 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1739T>C	p.Met580Thr	missense	Exon 17 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.888 AC: 134991 AN: 152028 Hom.: 61122 Cov.: 32

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.947

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.962

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.911

GnomAD2 exomes AF: 0.935 AC: 234686 AN: 251092 AF XY: 0.941

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.948

Gnomad ASJ exome AF: 0.952

Gnomad EAS exome AF: 0.808

Gnomad FIN exome AF: 0.938

Gnomad NFE exome AF: 0.984

Gnomad OTH exome AF: 0.953

GnomAD4 exome AF: 0.967 AC: 1413473 AN: 1461724 Hom.: 685876 Cov.: 69 AF XY: 0.967 AC XY: 703266 AN XY: 727186

African (AFR) AF: 0.679 AC: 22731 AN: 33480

American (AMR) AF: 0.943 AC: 42157 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.953 AC: 24899 AN: 26136

East Asian (EAS) AF: 0.818 AC: 32479 AN: 39700

South Asian (SAS) AF: 0.932 AC: 80408 AN: 86252

European-Finnish (FIN) AF: 0.936 AC: 49863 AN: 53270

Middle Eastern (MID) AF: 0.968 AC: 5585 AN: 5768

European-Non Finnish (NFE) AF: 0.988 AC: 1098270 AN: 1112006

Other (OTH) AF: 0.945 AC: 57081 AN: 60390

GnomAD4 genome AF: 0.888 AC: 135058 AN: 152146 Hom.: 61143 Cov.: 32 AF XY: 0.885 AC XY: 65849 AN XY: 74384

African (AFR) AF: 0.696 AC: 28864 AN: 41474

American (AMR) AF: 0.928 AC: 14199 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.947 AC: 3287 AN: 3472

East Asian (EAS) AF: 0.820 AC: 4232 AN: 5164

South Asian (SAS) AF: 0.919 AC: 4430 AN: 4818

European-Finnish (FIN) AF: 0.939 AC: 9959 AN: 10602

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.985 AC: 66976 AN: 68002

Other (OTH) AF: 0.910 AC: 1920 AN: 2110

Alfa AF: 0.957 Hom.: 92580

Bravo AF: 0.877

Asia WGS AF: 0.817 AC: 2840 AN: 3478

EpiCase AF: 0.984

EpiControl AF: 0.986

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (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	0.056
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.017
DANN	Benign	0.53
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.015	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.94	N
PhyloP100		-1.3
PROVEAN	Benign	0.22	N
REVEL	Benign	0.28
Sift	Benign	0.87	T
Sift4G	Benign	0.70	T
Varity_R		0.049
gMVP		0.34
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5253;

hg19: chr1-16380196;

COSMIC: COSV107483759;

COSMIC: COSV107483759;