NM_000085.5:c.641C>G

Variant names:

• chr1-16048568-C-G
• rs1889789
• NM_000085.5:c.641C>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.641C>G​(p.Ala214Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 151,752 control chromosomes in the GnomAD database, including 53,689 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. Synonymous variant affecting the same amino acid position (i.e. A214A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.83 (53689 hom., cov: 31)
  • Exomes 𝑓: 0.92 (614572 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.228
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2906515E-6).
• BP6: Variant 1-16048568-C-G is Benign according to our data. Variant chr1-16048568-C-G is described in ClinVar as Benign. ClinVar VariationId is 504916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.641C>G	p.Ala214Gly	missense	Exon 7 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.-404C>G		upstream_gene	N/A	NP_001159417.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.641C>G	p.Ala214Gly	missense	Exon 7 of 20	ENSP00000364831.5
	CLCNKB	ENST00000906263.1		c.695C>G	p.Ala232Gly	missense	Exon 8 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.695C>G	p.Ala232Gly	missense	Exon 8 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125197 AN: 151636 Hom.: 53660 Cov.: 31

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.896

Gnomad ASJ AF: 0.880

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.936

Gnomad FIN AF: 0.918

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.848

GnomAD2 exomes AF: 0.907 AC: 227210 AN: 250534 AF XY: 0.912

Gnomad AFR exome AF: 0.559

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.890

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.919

Gnomad NFE exome AF: 0.926

Gnomad OTH exome AF: 0.906

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.915 AC: 1337185 AN: 1461102 Hom.: 614572 Cov.: 63 AF XY: 0.917 AC XY: 666217 AN XY: 726860

African (AFR) AF: 0.549 AC: 18385 AN: 33458

American (AMR) AF: 0.932 AC: 41643 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.884 AC: 23093 AN: 26130

East Asian (EAS) AF: 1.00 AC: 39673 AN: 39690

South Asian (SAS) AF: 0.924 AC: 79708 AN: 86230

European-Finnish (FIN) AF: 0.918 AC: 48962 AN: 53342

Middle Eastern (MID) AF: 0.876 AC: 4821 AN: 5506

European-Non Finnish (NFE) AF: 0.923 AC: 1026657 AN: 1111708

Other (OTH) AF: 0.899 AC: 54243 AN: 60338

GnomAD4 genome AF: 0.826 AC: 125275 AN: 151752 Hom.: 53689 Cov.: 31 AF XY: 0.829 AC XY: 61461 AN XY: 74178

African (AFR) AF: 0.571 AC: 23552 AN: 41268

American (AMR) AF: 0.896 AC: 13690 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.880 AC: 3051 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5110 AN: 5114

South Asian (SAS) AF: 0.936 AC: 4509 AN: 4816

European-Finnish (FIN) AF: 0.918 AC: 9728 AN: 10592

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

European-Non Finnish (NFE) AF: 0.924 AC: 62753 AN: 67908

Other (OTH) AF: 0.850 AC: 1793 AN: 2110

Alfa AF: 0.898 Hom.: 15638

Bravo AF: 0.810

ExAC AF: 0.900 AC: 109279

Asia WGS AF: 0.948 AC: 3294 AN: 3478

EpiCase AF: 0.917

EpiControl AF: 0.922

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)
-	-	2	Bartter disease type 3 (2)
-	-	1	Bartter disease type 4B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.5
DANN	Benign	0.75
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.23
PROVEAN	Benign	0.82	N
REVEL	Benign	0.21
Sift	Benign	0.69	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.36
MPC		1.2
ClinPred		0.00043	T
GERP RS		2.7
PromoterAI		0.0030	Neutral
Varity_R		0.038
gMVP		0.26
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: rs1889789; hg19: chr1-16375063; COSMIC: COSV65159497; COSMIC: COSV65159497;