1-16044378-C-CACACACACACACACAT

Variant names:

• chr1-16044378-C-CACACACACACACACAT
• rs146972886
• NM_000085.5:c.-7-108_-7-107insACACACACACACACAT

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_-7-107insACACACACACACACAT 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 0.0053 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0050 (62 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 sas. GnomAd4 allele frequency = 0.00534 (807/151174) while in subpopulation SAS AF = 0.0103 (49/4744). AF 95% confidence interval is 0.00803. There are 4 homozygotes in GnomAd4. There are 393 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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_-7-107insACACACACACACACAT		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_-7-107insACACACACACACACAT		intron	N/A	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906274.1		c.-115_-114insACACACACACACACAT		5_prime_UTR	Exon 1 of 19	ENSP00000576333.1
	CLCNKB	ENST00000906263.1		c.-7-108_-7-107insACACACACACACACAT		intron	N/A	ENSP00000576322.1

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 807 AN: 151068 Hom.: 4 Cov.: 0

Gnomad AFR AF: 0.00172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00449

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.00403

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00804

Gnomad OTH AF: 0.00916

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00495 AC: 2911 AN: 587948 Hom.: 62 AF XY: 0.00517 AC XY: 1614 AN XY: 312006

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

African (AFR) AF: 0.00124 AC: 22 AN: 17796

American (AMR) AF: 0.00602 AC: 196 AN: 32570

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 45 AN: 18692

East Asian (EAS) AF: 0.0000967 AC: 3 AN: 31026

South Asian (SAS) AF: 0.00780 AC: 470 AN: 60250

European-Finnish (FIN) AF: 0.00310 AC: 122 AN: 39328

Middle Eastern (MID) AF: 0.0183 AC: 45 AN: 2456

European-Non Finnish (NFE) AF: 0.00525 AC: 1865 AN: 354960

Other (OTH) AF: 0.00463 AC: 143 AN: 30870

⚠️ 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: 0.00534 AC: 807 AN: 151174 Hom.: 4 Cov.: 0 AF XY: 0.00533 AC XY: 393 AN XY: 73768

African (AFR) AF: 0.00172 AC: 71 AN: 41322

American (AMR) AF: 0.00448 AC: 68 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3460

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5120

South Asian (SAS) AF: 0.0103 AC: 49 AN: 4744

European-Finnish (FIN) AF: 0.00403 AC: 42 AN: 10424

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00804 AC: 544 AN: 67650

Other (OTH) AF: 0.00907 AC: 19 AN: 2094

Alfa AF: 0.00186 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;