1-16044378-C-CACACACACACACAT

Variant names:

• chr1-16044378-C-CACACACACACACAT
• rs146972886
• NM_000085.5:c.-7-108_-7-107insACACACACACACAT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000085.5(CLCNKB):​c.-7-108_-7-107insACACACACACACAT 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2880 hom., cov: 0)
  • Exomes 𝑓: 0.14 (3209 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 intron
• Clinical Significance: 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-CACACACACACACAT is Benign according to our data. Variant chr1-16044378-C-CACACACACACACAT is described in ClinVar as Benign. ClinVar VariationId is 1269181.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27111 AN: 150902 Hom.: 2877 Cov.: 0

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.198

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.141 AC: 80768 AN: 571598 Hom.: 3209 AF XY: 0.144 AC XY: 43739 AN XY: 303036

African (AFR) AF: 0.0447 AC: 782 AN: 17510

American (AMR) AF: 0.212 AC: 6566 AN: 31042

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 3303 AN: 18144

East Asian (EAS) AF: 0.00776 AC: 240 AN: 30934

South Asian (SAS) AF: 0.192 AC: 10984 AN: 57064

European-Finnish (FIN) AF: 0.137 AC: 5272 AN: 38360

Middle Eastern (MID) AF: 0.162 AC: 389 AN: 2394

European-Non Finnish (NFE) AF: 0.141 AC: 48926 AN: 346086

Other (OTH) AF: 0.143 AC: 4306 AN: 30064

GnomAD4 genome AF: 0.180 AC: 27120 AN: 151010 Hom.: 2880 Cov.: 0 AF XY: 0.183 AC XY: 13495 AN XY: 73688

African (AFR) AF: 0.0745 AC: 3076 AN: 41300

American (AMR) AF: 0.273 AC: 4137 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 909 AN: 3458

East Asian (EAS) AF: 0.0162 AC: 83 AN: 5118

South Asian (SAS) AF: 0.276 AC: 1309 AN: 4736

European-Finnish (FIN) AF: 0.215 AC: 2234 AN: 10390

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14513 AN: 67574

Other (OTH) AF: 0.200 AC: 419 AN: 2094

Alfa AF: 0.151 Hom.: 246

ClinVar

ClinVar submissions

Significance: 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 (auto)

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;