rs1057854

Variant names:

• chr1-16057187-G-C
• rs1057854
• NM_000085.5:c.*271G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000085.5(CLCNKB):​c.*271G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (224 hom., cov: 41)
  • Exomes 𝑓: 0.28 (114 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKB NM_000085.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.23
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025365949).
• BP6: Variant 1-16057187-G-C is Benign according to our data. Variant chr1-16057187-G-C is described in ClinVar as Benign. ClinVar VariationId is 402540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKB	NM_000085.5	c.*271G>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000375679.9	NP_000076.2
CLCNKB	NM_001165945.2	c.*271G>C		3_prime_UTR_variant	Exon 13 of 13		NP_001159417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKB	ENST00000375679.9	c.*271G>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_000085.5	ENSP00000364831.5

Frequencies

GnomAD3 genomes AF: 0.329 AC: 46820 AN: 142470 Hom.: 223 Cov.: 41

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.334

GnomAD2 exomes AF: 0.298 AC: 41736 AN: 140152 AF XY: 0.301

Gnomad AFR exome AF: 0.402

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.424

Gnomad FIN exome AF: 0.292

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.301

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.275 AC: 126136 AN: 458492 Hom.: 114 Cov.: 0 AF XY: 0.277 AC XY: 69246 AN XY: 250084

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.383 AC: 5023 AN: 13108

American (AMR) AF: 0.213 AC: 6394 AN: 30082

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 4139 AN: 16646

East Asian (EAS) AF: 0.405 AC: 9328 AN: 23020

South Asian (SAS) AF: 0.285 AC: 16287 AN: 57194

European-Finnish (FIN) AF: 0.257 AC: 10206 AN: 39642

Middle Eastern (MID) AF: 0.288 AC: 992 AN: 3440

European-Non Finnish (NFE) AF: 0.267 AC: 66989 AN: 251300

Other (OTH) AF: 0.282 AC: 6778 AN: 24060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.329 AC: 46847 AN: 142580 Hom.: 224 Cov.: 41 AF XY: 0.326 AC XY: 22729 AN XY: 69680

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.407 AC: 15910 AN: 39062

American (AMR) AF: 0.258 AC: 3699 AN: 14324

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 896 AN: 3282

East Asian (EAS) AF: 0.439 AC: 2082 AN: 4746

South Asian (SAS) AF: 0.291 AC: 1280 AN: 4406

European-Finnish (FIN) AF: 0.277 AC: 2762 AN: 9956

Middle Eastern (MID) AF: 0.358 AC: 96 AN: 268

European-Non Finnish (NFE) AF: 0.302 AC: 19248 AN: 63722

Other (OTH) AF: 0.333 AC: 653 AN: 1960

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.319 Hom.: 21

ExAC AF: 0.224 AC: 5374

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

not provided Benign:1

-

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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.024
DANN	Benign	0.31
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.98	T
PhyloP100		-3.2
Sift4G	Uncertain	0.0090	D
Vest4		0.090
ClinPred		0.0074	T
GERP RS		-4.9
Mutation Taster		=100/0	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: rs1057854; hg19: chr1-16383682; COSMIC: COSV65152876; COSMIC: COSV65152876;