rs387907412

Variant names:

• chr1-16044563-C-A
• rs387907412
• NM_000085.5:c.71C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-16044563-C-A
• chr1-16044563-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000085.5(CLCNKB):​c.71C>A​(p.Pro24His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.71C>A	p.Pro24His	missense	Exon 2 of 20	NP_000076.2	P51801-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.71C>A	p.Pro24His	missense	Exon 2 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.71C>A	p.Pro24His	missense	Exon 2 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.71C>A	p.Pro24His	missense	Exon 2 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.88e-7 AC: 1 AN: 1453266 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721784

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 43262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25818

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39384

South Asian (SAS) AF: 0.00 AC: 0 AN: 83784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108838

Other (OTH) AF: 0.00 AC: 0 AN: 60084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0074	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.0020
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.68		Loss of helix (P = 0.0237)
MVP		0.88
MPC		0.25
ClinPred		0.97	D
GERP RS		3.1
Varity_R		0.61
gMVP		0.53
Mutation Taster		=62/38	polymorphism

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: rs387907412; hg19: chr1-16371058;