rs35351345

chr1-16051552-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_Moderate BP6 BS1 BS2

The NM_000085.5(CLCNKB):c.1297+5G>T variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00705 in 1,614,038 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (45 hom.)
• Consequence: CLCNKB NM_000085.5 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 6.37

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 1-16051552-G-T is Benign according to our data. Variant chr1-16051552-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447090.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=1}. Variant chr1-16051552-G-T is described in Lovd as [Benign]. Variant chr1-16051552-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00522 (795/152236) while in subpopulation NFE AF= 0.00816 (555/68004). AF 95% confidence interval is 0.0076. There are 2 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKB	NM_000085.5	c.1297+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000375679.9
CLCNKB	NM_001165945.2	c.790+5G>T		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKB	ENST00000375679.9	c.1297+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_000085.5	P4

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152118 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00570 AC: 1434 AN: 251492 Hom.: 6 AF XY: 0.00566 AC XY: 769 AN XY: 135920

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00927

Gnomad OTH exome AF: 0.00782

GnomAD4 exome AF: 0.00724 AC: 10587 AN: 1461802 Hom.: 45 Cov.: 34 AF XY: 0.00716 AC XY: 5205 AN XY: 727206

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00834

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.00841

Gnomad4 OTH exome AF: 0.00684

GnomAD4 genome AF: 0.00522 AC: 795 AN: 152236 Hom.: 2 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74438

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00816

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00781 Hom.: 2

Bravo AF: 0.00554

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.0106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CLCNKB: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2022	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1 Benign:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 03, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs35351345; hg19: chr1-16378047;