NM_000085.5:c.1391G>C

Variant names:

• chr1-16051803-G-C
• rs763456347
• NM_000085.5:c.1391G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000085.5(CLCNKB):​c.1391G>C​(p.Gly464Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.60
• Publications: 1 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000085.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

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.1391G>C	p.Gly464Ala	missense	Exon 14 of 20	NP_000076.2
	CLCNKB	NM_001165945.2		c.884G>C	p.Gly295Ala	missense	Exon 7 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.1391G>C	p.Gly464Ala	missense	Exon 14 of 20	ENSP00000364831.5
	CLCNKB	ENST00000906263.1		c.1445G>C	p.Gly482Ala	missense	Exon 15 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1445G>C	p.Gly482Ala	missense	Exon 15 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460508 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726680

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.6
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.016	D
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.72
MutPred		0.92		Loss of sheet (P = 0.0817)
MVP		0.98
MPC		0.53
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.41
gMVP		0.67
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs763456347; hg19: chr1-16378298; COSMIC: COSV65160020; COSMIC: COSV65160020;