NM_000085.5:c.324A>G

Variant names:

• chr1-16046629-A-G
• rs5257
• NM_000085.5:c.324A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000085.5(CLCNKB):​c.324A>G​(p.Ser108Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,613,688 control chromosomes in the GnomAD database, including 520,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S108S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.70 (40556 hom., cov: 32)
  • Exomes 𝑓: 0.81 (480017 hom.)
• Consequence: CLCNKB NM_000085.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.89
• Publications: 32 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 -16 ACMG points.

• BP6: Variant 1-16046629-A-G is Benign according to our data. Variant chr1-16046629-A-G is described in ClinVar as Benign. ClinVar VariationId is 447104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 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.324A>G	p.Ser108Ser	synonymous	Exon 4 of 20	NP_000076.2	P51801-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKB	ENST00000375679.9	TSL:1 MANE Select	c.324A>G	p.Ser108Ser	synonymous	Exon 4 of 20	ENSP00000364831.5	P51801-1
	CLCNKB	ENST00000906263.1		c.378A>G	p.Ser126Ser	synonymous	Exon 5 of 21	ENSP00000576322.1
	CLCNKB	ENST00000906270.1		c.378A>G	p.Ser126Ser	synonymous	Exon 5 of 21	ENSP00000576329.1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106696 AN: 151836 Hom.: 40534 Cov.: 32

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.856

Gnomad AMR AF: 0.829

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.891

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.809

Gnomad OTH AF: 0.742

GnomAD2 exomes AF: 0.812 AC: 204128 AN: 251366 AF XY: 0.819

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.899

Gnomad ASJ exome AF: 0.835

Gnomad EAS exome AF: 0.989

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.809

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.806 AC: 1178779 AN: 1461734 Hom.: 480017 Cov.: 58 AF XY: 0.810 AC XY: 588877 AN XY: 727184

African (AFR) AF: 0.366 AC: 12260 AN: 33474

American (AMR) AF: 0.889 AC: 39759 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 21542 AN: 26134

East Asian (EAS) AF: 0.986 AC: 39139 AN: 39700

South Asian (SAS) AF: 0.874 AC: 75355 AN: 86258

European-Finnish (FIN) AF: 0.767 AC: 40965 AN: 53406

Middle Eastern (MID) AF: 0.807 AC: 4654 AN: 5768

European-Non Finnish (NFE) AF: 0.807 AC: 896984 AN: 1111876

Other (OTH) AF: 0.797 AC: 48121 AN: 60394

GnomAD4 genome AF: 0.702 AC: 106740 AN: 151954 Hom.: 40556 Cov.: 32 AF XY: 0.709 AC XY: 52631 AN XY: 74266

African (AFR) AF: 0.389 AC: 16099 AN: 41376

American (AMR) AF: 0.829 AC: 12672 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2828 AN: 3470

East Asian (EAS) AF: 0.988 AC: 5094 AN: 5158

South Asian (SAS) AF: 0.892 AC: 4290 AN: 4810

European-Finnish (FIN) AF: 0.773 AC: 8163 AN: 10556

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.809 AC: 55009 AN: 67984

Other (OTH) AF: 0.745 AC: 1575 AN: 2114

Alfa AF: 0.778 Hom.: 191666

Bravo AF: 0.693

Asia WGS AF: 0.898 AC: 3121 AN: 3478

EpiCase AF: 0.815

EpiControl AF: 0.817

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Bartter disease type 3 (1)
-	-	1	Bartter disease type 4B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.18
DANN	Benign	0.33
PhyloP100		-3.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 13

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

Other links and lift over

dbSNP: rs5257; hg19: chr1-16373124; COSMIC: COSV108229015; COSMIC: COSV108229015;