NM_000085.5:c.656-105G>A

Variant names:

• chr1-16049015-G-A
• rs11588392
• NM_000085.5:c.656-105G>A

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.656-105G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,604,684 control chromosomes in the GnomAD database, including 3,984 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.099 (1345 hom., cov: 34)
  • Exomes 𝑓: 0.049 (2639 hom.)
• Consequence: CLCNKB NM_000085.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.259
• Publications: 8 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.005407542).
• BP6: Variant 1-16049015-G-A is Benign according to our data. Variant chr1-16049015-G-A is described in ClinVar as Benign. ClinVar VariationId is 504913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	NM_000085.5	MANE Select	c.656-105G>A		intron	N/A	NP_000076.2
	CLCNKB	NM_001165945.2		c.44G>A	p.Gly15Glu	missense	Exon 1 of 13	NP_001159417.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.656-105G>A		intron	N/A	ENSP00000364831.5
	CLCNKB	ENST00000375667.7	TSL:2	c.44G>A	p.Gly15Glu	missense	Exon 1 of 13	ENSP00000364819.3
	CLCNKB	ENST00000683606.1		n.166G>A		non_coding_transcript_exon	Exon 1 of 13

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15020 AN: 152040 Hom.: 1343 Cov.: 34

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0623

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0833

GnomAD2 exomes AF: 0.0531 AC: 13017 AN: 245060 AF XY: 0.0499

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0917

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0719

Gnomad NFE exome AF: 0.0422

Gnomad OTH exome AF: 0.0558

GnomAD4 exome AF: 0.0488 AC: 70823 AN: 1452526 Hom.: 2639 Cov.: 54 AF XY: 0.0476 AC XY: 34375 AN XY: 721706

African (AFR) AF: 0.245 AC: 8168 AN: 33302

American (AMR) AF: 0.0378 AC: 1680 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.0977 AC: 2538 AN: 25966

East Asian (EAS) AF: 0.000329 AC: 13 AN: 39556

South Asian (SAS) AF: 0.0259 AC: 2231 AN: 86030

European-Finnish (FIN) AF: 0.0718 AC: 3629 AN: 50564

Middle Eastern (MID) AF: 0.0623 AC: 313 AN: 5024

European-Non Finnish (NFE) AF: 0.0439 AC: 48647 AN: 1107700

Other (OTH) AF: 0.0601 AC: 3604 AN: 59960

GnomAD4 genome AF: 0.0988 AC: 15036 AN: 152158 Hom.: 1345 Cov.: 34 AF XY: 0.0972 AC XY: 7228 AN XY: 74392

African (AFR) AF: 0.233 AC: 9681 AN: 41468

American (AMR) AF: 0.0622 AC: 952 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 360 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.0219 AC: 106 AN: 4830

European-Finnish (FIN) AF: 0.0712 AC: 756 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0434 AC: 2954 AN: 67990

Other (OTH) AF: 0.0824 AC: 174 AN: 2112

Alfa AF: 0.0571 Hom.: 481

Bravo AF: 0.105

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0522 AC: 201

ESP6500AA AF: 0.214 AC: 296

ESP6500EA AF: 0.0469 AC: 149

ExAC AF: 0.0545 AC: 6615

Asia WGS AF: 0.0230 AC: 83 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 18, 2020

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

not specified Benign:1

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly15Glu in exon 1 of CLCNKB: This variant is not expected to have clinical si gnificance because it has been identified in 26.32% (2312/8784) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs11588392).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.3
DANN	Benign	0.93
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.26
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.044
ClinPred		0.012	T
GERP RS		-4.7
PromoterAI		0.037	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs11588392; hg19: chr1-16375510; COSMIC: COSV107483960; COSMIC: COSV107483960;