1-16044378-C-CACACACAT

Variant names:

• chr1-16044378-C-CACACACAT
• rs146972886
• NM_000085.5:c.-7-108_-7-107insACACACAT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000085.5(CLCNKB):​c.-7-108_-7-107insACACACAT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 0)
  • Exomes 𝑓: 0.064 (641 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 2 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00675 (1019/150936) while in subpopulation AMR AF = 0.0116 (176/15150). AF 95% confidence interval is 0.0102. There are 7 homozygotes in GnomAd4. There are 467 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.-7-108_-7-107insACACACAT		intron	N/A	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.-7-108_-7-107insACACACAT		intron	N/A	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906274.1		c.-115_-114insACACACAT		5_prime_UTR	Exon 1 of 19	ENSP00000576333.1
	CLCNKB	ENST00000906263.1		c.-7-108_-7-107insACACACAT		intron	N/A	ENSP00000576322.1

Frequencies

GnomAD3 genomes AF: 0.00676 AC: 1020 AN: 150830 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.0111

Gnomad SAS AF: 0.00652

Gnomad FIN AF: 0.00262

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00898

Gnomad OTH AF: 0.00725

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0639 AC: 36527 AN: 571548 Hom.: 641 AF XY: 0.0633 AC XY: 19210 AN XY: 303266

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

African (AFR) AF: 0.0148 AC: 260 AN: 17616

American (AMR) AF: 0.0642 AC: 2038 AN: 31752

Ashkenazi Jewish (ASJ) AF: 0.0497 AC: 905 AN: 18204

East Asian (EAS) AF: 0.200 AC: 5643 AN: 28206

South Asian (SAS) AF: 0.0576 AC: 3376 AN: 58580

European-Finnish (FIN) AF: 0.0460 AC: 1765 AN: 38336

Middle Eastern (MID) AF: 0.0598 AC: 143 AN: 2392

European-Non Finnish (NFE) AF: 0.0593 AC: 20555 AN: 346422

Other (OTH) AF: 0.0613 AC: 1842 AN: 30040

⚠️ 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 AF: 0.00675 AC: 1019 AN: 150936 Hom.: 7 Cov.: 0 AF XY: 0.00634 AC XY: 467 AN XY: 73618

African (AFR) AF: 0.00240 AC: 99 AN: 41318

American (AMR) AF: 0.0116 AC: 176 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 6 AN: 3458

East Asian (EAS) AF: 0.0112 AC: 57 AN: 5102

South Asian (SAS) AF: 0.00654 AC: 31 AN: 4740

European-Finnish (FIN) AF: 0.00262 AC: 27 AN: 10324

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00898 AC: 607 AN: 67558

Other (OTH) AF: 0.00718 AC: 15 AN: 2090

Alfa AF: 0.00 Hom.: 246

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.086
Mutation Taster		=100/0	polymorphism

Splicing

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: rs146972886; hg19: chr1-16370873;