rs35351345

Positions:

chr1-16051552-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_ModerateBP6BS1BS2

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:2B:4

Conservation

PhyloP100: 6.37

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=1, Benign=1, Uncertain_significance=3}. 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 GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCNKB	NM_000085.5 linkuse as main transcript	c.1297+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000375679.9	NP_000076.2
CLCNKB	NM_001165945.2 linkuse as main transcript	c.790+5G>T		splice_donor_5th_base_variant, intron_variant			NP_001159417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 linkuse as main transcript	c.1297+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_000085.5	ENSP00000364831	P4	P51801-1

Frequencies

GnomAD3 genomes

AF:

0.00523

AC:

796

AN:

152118

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00566

AC XY:

769

AN XY:

135920

show subpopulations

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.:

Cov.:

AF XY:

0.00716

AC XY:

5205

AN XY:

727206

show subpopulations

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.:

Cov.:

AF XY:

0.00478

AC XY:

356

AN XY:

74438

show subpopulations

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.:

Bravo

AF:

0.00554

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00932

EpiControl

AF:

0.0106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CLCNKB: PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2024	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 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:1Benign: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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over