1-16044378-C-CACACACACACAT

Variant names:

• chr1-16044378-C-CACACACACACAT
• rs146972886
• NM_000085.5:c.-7-108_-7-107insACACACACACAT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000085.5(CLCNKB):​c.-7-108_-7-107insACACACACACAT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (40 hom., cov: 0)
  • Exomes 𝑓: 0.051 (849 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 1-16044378-C-CACACACACACAT is Benign according to our data. Variant chr1-16044378-C-CACACACACACAT is described in ClinVar as Likely_benign. ClinVar VariationId is 1197677.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0195 (2942/151014) while in subpopulation NFE AF = 0.0308 (2081/67600). AF 95% confidence interval is 0.0297. There are 40 homozygotes in GnomAd4. There are 1340 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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_-7-107insACACACACACAT		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_-7-107insACACACACACAT		intron	N/A	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906274.1		c.-115_-114insACACACACACAT		5_prime_UTR	Exon 1 of 19	ENSP00000576333.1
	CLCNKB	ENST00000906263.1		c.-7-108_-7-107insACACACACACAT		intron	N/A	ENSP00000576322.1

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2940 AN: 150908 Hom.: 40 Cov.: 0

Gnomad AFR AF: 0.00721

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0140

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0308

Gnomad OTH AF: 0.0169

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0508 AC: 29352 AN: 577912 Hom.: 849 AF XY: 0.0523 AC XY: 16027 AN XY: 306574

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

African (AFR) AF: 0.0117 AC: 207 AN: 17630

American (AMR) AF: 0.0705 AC: 2244 AN: 31810

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 970 AN: 18356

East Asian (EAS) AF: 0.0204 AC: 628 AN: 30834

South Asian (SAS) AF: 0.0618 AC: 3627 AN: 58686

European-Finnish (FIN) AF: 0.0313 AC: 1215 AN: 38774

Middle Eastern (MID) AF: 0.0574 AC: 139 AN: 2420

European-Non Finnish (NFE) AF: 0.0540 AC: 18847 AN: 349024

Other (OTH) AF: 0.0486 AC: 1475 AN: 30378

⚠️ 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: 0.0195 AC: 2942 AN: 151014 Hom.: 40 Cov.: 0 AF XY: 0.0182 AC XY: 1340 AN XY: 73678

African (AFR) AF: 0.00724 AC: 299 AN: 41322

American (AMR) AF: 0.0195 AC: 295 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3458

East Asian (EAS) AF: 0.0141 AC: 72 AN: 5116

South Asian (SAS) AF: 0.0160 AC: 76 AN: 4740

European-Finnish (FIN) AF: 0.00414 AC: 43 AN: 10374

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0308 AC: 2081 AN: 67600

Other (OTH) AF: 0.0172 AC: 36 AN: 2088

Alfa AF: 0.00822 Hom.: 246

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

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

Other links and lift over

dbSNP: rs146972886; hg19: chr1-16370873;