1-16044378-C-CACACAT

Variant names:

• chr1-16044378-C-CACACAT
• rs146972886
• NM_000085.5:c.-7-108_-7-107insACACAT

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_-7-107insACACAT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (67 hom., cov: 0)
  • Exomes 𝑓: 0.026 (627 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-CACACAT is Benign according to our data. Variant chr1-16044378-C-CACACAT is described in ClinVar as Benign. ClinVar VariationId is 3910069.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0223 (3366/151166) while in subpopulation NFE AF = 0.029 (1959/67648). AF 95% confidence interval is 0.0279. There are 67 homozygotes in GnomAd4. There are 1678 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 67 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_-7-107insACACAT		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_-7-107insACACAT		intron	N/A	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906274.1		c.-115_-114insACACAT		5_prime_UTR	Exon 1 of 19	ENSP00000576333.1
	CLCNKB	ENST00000906263.1		c.-7-108_-7-107insACACAT		intron	N/A	ENSP00000576322.1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3365 AN: 151058 Hom.: 67 Cov.: 0

Gnomad AFR AF: 0.00534

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.0673

Gnomad EAS AF: 0.00526

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0251

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0262 AC: 15333 AN: 585262 Hom.: 627 AF XY: 0.0266 AC XY: 8249 AN XY: 310550

African (AFR) AF: 0.00495 AC: 88 AN: 17784

American (AMR) AF: 0.0142 AC: 461 AN: 32484

Ashkenazi Jewish (ASJ) AF: 0.0579 AC: 1074 AN: 18562

East Asian (EAS) AF: 0.00713 AC: 217 AN: 30428

South Asian (SAS) AF: 0.0266 AC: 1597 AN: 60128

European-Finnish (FIN) AF: 0.0320 AC: 1256 AN: 39192

Middle Eastern (MID) AF: 0.0322 AC: 79 AN: 2454

European-Non Finnish (NFE) AF: 0.0276 AC: 9762 AN: 353528

Other (OTH) AF: 0.0260 AC: 799 AN: 30702

GnomAD4 genome AF: 0.0223 AC: 3366 AN: 151166 Hom.: 67 Cov.: 0 AF XY: 0.0227 AC XY: 1678 AN XY: 73760

African (AFR) AF: 0.00535 AC: 221 AN: 41328

American (AMR) AF: 0.0181 AC: 274 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.0673 AC: 233 AN: 3460

East Asian (EAS) AF: 0.00527 AC: 27 AN: 5120

South Asian (SAS) AF: 0.0221 AC: 105 AN: 4746

European-Finnish (FIN) AF: 0.0360 AC: 375 AN: 10416

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0290 AC: 1959 AN: 67648

Other (OTH) AF: 0.0249 AC: 52 AN: 2090

Alfa AF: 0.0190 Hom.: 246

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (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;