chr1-16044378-C-CACACACACACACACACAT

Variant names:

• chr1-16044378-C-CACACACACACACACACAT
• rs146972886
• NM_000085.5:c.-7-108_-7-107insACACACACACACACACAT

Variant summary

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

The NM_000085.5(CLCNKB):​c.-7-108_-7-107insACACACACACACACACAT 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (18 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: Uncertain_significance. The variant received 0 ACMG points.

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

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 222 AN: 151076 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000534

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000631

Gnomad FIN AF: 0.00326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.00386

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00106 AC: 627 AN: 588808 Hom.: 18 AF XY: 0.00102 AC XY: 318 AN XY: 312476

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

African (AFR) AF: 0.000225 AC: 4 AN: 17800

American (AMR) AF: 0.00113 AC: 37 AN: 32632

Ashkenazi Jewish (ASJ) AF: 0.000802 AC: 15 AN: 18702

East Asian (EAS) AF: 0.0000322 AC: 1 AN: 31028

South Asian (SAS) AF: 0.000811 AC: 49 AN: 60442

European-Finnish (FIN) AF: 0.00214 AC: 84 AN: 39342

Middle Eastern (MID) AF: 0.000406 AC: 1 AN: 2464

European-Non Finnish (NFE) AF: 0.00113 AC: 400 AN: 355480

Other (OTH) AF: 0.00116 AC: 36 AN: 30918

⚠️ 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: 0.00147 AC: 222 AN: 151184 Hom.: 0 Cov.: 0 AF XY: 0.00123 AC XY: 91 AN XY: 73776

African (AFR) AF: 0.000532 AC: 22 AN: 41328

American (AMR) AF: 0.00106 AC: 16 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.000632 AC: 3 AN: 4746

European-Finnish (FIN) AF: 0.00326 AC: 34 AN: 10422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00205 AC: 139 AN: 67654

Other (OTH) AF: 0.00382 AC: 8 AN: 2094

Alfa AF: 0.00172 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

Other links and lift over

dbSNP: rs146972886; hg19: chr1-16370873;