Genetic Variant NM_000085.5:c.1254C>T (chr1-16051504-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000085.5(CLCNKB):c.1254C>T(p.Thr418Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,610,352 control chromosomes in the GnomAD database, including 11,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1679 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10057 hom. )

Consequence

CLCNKB
NM_000085.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.62

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 1-16051504-C-T is Benign according to our data. Variant chr1-16051504-C-T is described in ClinVar as [Benign]. Clinvar id is 585698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-16051504-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.62 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5 link	c.1254C>T	p.Thr418Thr	synonymous_variant	Exon 13 of 20	ENST00000375679.9	NP_000076.2	P51801-1A8K8H0
CLCNKB	NM_001165945.2 link	c.747C>T	p.Thr249Thr	synonymous_variant	Exon 6 of 13		NP_001159417.2	P51801-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9 link	c.1254C>T	p.Thr418Thr	synonymous_variant	Exon 13 of 20	1	NM_000085.5	ENSP00000364831.5		P51801-1

Frequencies

GnomAD3 genomes

AF:

0.132

AC:

20088

AN:

152014

Hom.:

1663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.0749

Gnomad ASJ

AF:

0.0567

Gnomad EAS

AF:

0.0114

Gnomad SAS

AF:

0.0443

Gnomad FIN

AF:

0.120

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.119

GnomAD3 exomes

AF:

0.0961

AC:

24157

AN:

251452

Hom.:

1542

AF XY:

0.0935

AC XY:

12712

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.0481

Gnomad ASJ exome

AF:

0.0507

Gnomad EAS exome

AF:

0.0105

Gnomad SAS exome

AF:

0.0489

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.117

Gnomad OTH exome

AF:

0.0969

GnomAD4 exome

AF:

0.111

AC:

161443

AN:

1458220

Hom.:

10057

Cov.:

AF XY:

0.108

AC XY:

78524

AN XY:

725614

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.0522

Gnomad4 ASJ exome

AF:

0.0531

Gnomad4 EAS exome

AF:

0.0137

Gnomad4 SAS exome

AF:

0.0488

Gnomad4 FIN exome

AF:

0.126

Gnomad4 NFE exome

AF:

0.119

Gnomad4 OTH exome

AF:

0.106

GnomAD4 genome

AF:

0.132

AC:

20145

AN:

152132

Hom.:

1679

Cov.:

AF XY:

0.128

AC XY:

9550

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.217

Gnomad4 AMR

AF:

0.0748

Gnomad4 ASJ

AF:

0.0567

Gnomad4 EAS

AF:

0.0116

Gnomad4 SAS

AF:

0.0442

Gnomad4 FIN

AF:

0.120

Gnomad4 NFE

AF:

0.117

Gnomad4 OTH

AF:

0.117

Alfa

AF:

0.0988

Hom.:

549

Bravo

AF:

0.132

Asia WGS

AF:

0.0540

AC:

189

AN:

3478

EpiCase

AF:

0.108

EpiControl

AF:

0.107

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.084

DANN

Benign

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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