rs6650119

Variant names:

• chr1-16051505-A-G
• rs6650119
• NM_000085.5:c.1255A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-16051505-A-G
• chr1-16051505-A-C

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.1255A>G​(p.Ile419Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,610,144 control chromosomes in the GnomAD database, including 11,742 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. I419I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1682 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10060 hom.)
• Consequence: CLCNKB NM_000085.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.24
• Publications: 10 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 (MetaRNN=0.0020792186).
• BP6: Variant 1-16051505-A-G is Benign according to our data. Variant chr1-16051505-A-G is described in ClinVar as Benign. ClinVar VariationId is 585699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 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.1255A>G	p.Ile419Val	missense	Exon 13 of 20	NP_000076.2	P51801-1
	CLCNKB	NM_001165945.2		c.748A>G	p.Ile250Val	missense	Exon 6 of 13	NP_001159417.2	P51801-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.1255A>G	p.Ile419Val	missense	Exon 13 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.1309A>G	p.Ile437Val	missense	Exon 14 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.1309A>G	p.Ile437Val	missense	Exon 14 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20095 AN: 151802 Hom.: 1666 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0750

Gnomad ASJ AF: 0.0569

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.0445

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.0961 AC: 24163 AN: 251458 AF XY: 0.0936

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 FIN exome AF: 0.129

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.111 AC: 161465 AN: 1458224 Hom.: 10060 Cov.: 34 AF XY: 0.108 AC XY: 78524 AN XY: 725604

African (AFR) AF: 0.220 AC: 7341 AN: 33360

American (AMR) AF: 0.0522 AC: 2333 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 1386 AN: 26120

East Asian (EAS) AF: 0.0138 AC: 546 AN: 39698

South Asian (SAS) AF: 0.0488 AC: 4207 AN: 86232

European-Finnish (FIN) AF: 0.126 AC: 6750 AN: 53410

Middle Eastern (MID) AF: 0.0738 AC: 425 AN: 5760

European-Non Finnish (NFE) AF: 0.119 AC: 132110 AN: 1108632

Other (OTH) AF: 0.106 AC: 6367 AN: 60292

GnomAD4 genome AF: 0.133 AC: 20152 AN: 151920 Hom.: 1682 Cov.: 32 AF XY: 0.129 AC XY: 9555 AN XY: 74276

African (AFR) AF: 0.217 AC: 8991 AN: 41390

American (AMR) AF: 0.0748 AC: 1144 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 197 AN: 3464

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5152

South Asian (SAS) AF: 0.0443 AC: 213 AN: 4806

European-Finnish (FIN) AF: 0.121 AC: 1275 AN: 10578

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7939 AN: 67932

Other (OTH) AF: 0.117 AC: 247 AN: 2108

Alfa AF: 0.108 Hom.: 1034

Bravo AF: 0.132

TwinsUK AF: 0.119 AC: 443

ALSPAC AF: 0.125 AC: 480

ESP6500AA AF: 0.197 AC: 868

ESP6500EA AF: 0.0966 AC: 831

ExAC AF: 0.102 AC: 12325

Asia WGS AF: 0.0540 AC: 189 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.107

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.2
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.16
Sift	Benign	0.074	T
Sift4G	Benign	0.20	T
Polyphen		0.0050	B
Vest4		0.073
MPC		0.12
ClinPred		0.0038	T
GERP RS		2.0
Varity_R		0.062
gMVP		0.44
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6650119; hg19: chr1-16378000; COSMIC: COSV65162284; COSMIC: COSV65162284;