rs1889788

Variant names:

• chr1-16048499-C-T
• rs1889788
• NM_000085.5:c.577-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-16048499-C-T
• chr1-16048499-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000085.5(CLCNKB):​c.577-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 151,938 control chromosomes in the GnomAD database, including 40,346 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (40346 hom., cov: 31)
  • Exomes 𝑓: 0.81 (478251 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001950
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.322
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-16048499-C-T is Benign according to our data. Variant chr1-16048499-C-T is described in ClinVar as Benign. ClinVar VariationId is 381050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 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.577-5C>T		splice_region 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.577-5C>T		splice_region intron	N/A	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.631-5C>T		splice_region intron	N/A	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.631-5C>T		splice_region intron	N/A	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106363 AN: 151820 Hom.: 40322 Cov.: 31

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.827

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.739

GnomAD2 exomes AF: 0.810 AC: 203324 AN: 250886 AF XY: 0.817

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.899

Gnomad ASJ exome AF: 0.824

Gnomad EAS exome AF: 0.989

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.808

Gnomad OTH exome AF: 0.811

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.805 AC: 1176330 AN: 1461204 Hom.: 478251 Cov.: 57 AF XY: 0.808 AC XY: 587645 AN XY: 726898

African (AFR) AF: 0.364 AC: 12175 AN: 33460

American (AMR) AF: 0.888 AC: 39696 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 21294 AN: 26132

East Asian (EAS) AF: 0.986 AC: 39136 AN: 39698

South Asian (SAS) AF: 0.873 AC: 75272 AN: 86230

European-Finnish (FIN) AF: 0.767 AC: 40927 AN: 53390

Middle Eastern (MID) AF: 0.804 AC: 4422 AN: 5502

European-Non Finnish (NFE) AF: 0.805 AC: 895441 AN: 1111744

Other (OTH) AF: 0.795 AC: 47967 AN: 60336

GnomAD4 genome AF: 0.700 AC: 106410 AN: 151938 Hom.: 40346 Cov.: 31 AF XY: 0.707 AC XY: 52497 AN XY: 74274

African (AFR) AF: 0.386 AC: 15992 AN: 41396

American (AMR) AF: 0.827 AC: 12639 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2793 AN: 3466

East Asian (EAS) AF: 0.988 AC: 5074 AN: 5138

South Asian (SAS) AF: 0.889 AC: 4287 AN: 4820

European-Finnish (FIN) AF: 0.773 AC: 8184 AN: 10584

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.808 AC: 54870 AN: 67944

Other (OTH) AF: 0.742 AC: 1565 AN: 2108

Alfa AF: 0.748 Hom.: 18567

Bravo AF: 0.691

Asia WGS AF: 0.899 AC: 3120 AN: 3476

EpiCase AF: 0.814

EpiControl AF: 0.816

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Bartter disease type 3 (1)
-	-	1	Bartter disease type 4B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
DANN	Benign	0.75
PhyloP100		-0.32
PromoterAI		0.048	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1889788;

hg19: chr1-16374994;

COSMIC: COSV65161773;

COSMIC: COSV65161773;