chr1-16055708-C-T

Variant names:

• chr1-16055708-C-T
• rs376998876
• NM_000085.5:c.1879C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000085.5(CLCNKB):​c.1879C>T​(p.Pro627Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. P627T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.332
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17497641).

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.1879C>T	p.Pro627Ser	missense	Exon 18 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.1369C>T	p.Pro457Ser	missense	Exon 11 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.1879C>T	p.Pro627Ser	missense	Exon 18 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.1933C>T	p.Pro645Ser	missense	Exon 19 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1930C>T	p.Pro644Ser	missense	Exon 19 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251134 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461580 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

⚠️ 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: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.33
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.25
Sift	Benign	0.23	T
Sift4G	Benign	0.43	T
Polyphen		0.022	B
Vest4		0.26
MutPred		0.39		Loss of helix (P = 0.0626)
MVP		0.92
MPC		0.14
ClinPred		0.10	T
GERP RS		3.8
Varity_R		0.042
gMVP		0.37
Mutation Taster		=87/13	polymorphism

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: rs376998876; hg19: chr1-16382203;