rs1486642291

Variant names:

• chr1-16028019-G-T
• rs1486642291
• NM_004070.4:c.868G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004070.4(CLCNKA):​c.868G>T​(p.Gly290Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000248 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLCNKA NM_004070.4 missense, splice_region
• Scores: Splicing: ADA: 0.002587
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36
• Publications: 0 publications found

Genes affected

CLCNKA (HGNC:2026): (chloride voltage-gated channel Ka) This gene is a member of the CLC family of voltage-gated chloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit called barttin to form a functional channel. It is thought to function in salt reabsorption in the kidney and potassium recycling in the inner ear. The gene is highly similar to CLCNKB, which is located 10 kb downstream from this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CLCNKA Gene-Disease associations (from GenCC):

• Bartter disease type 4B

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics
• Bartter syndrome type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3157635).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004070.4. 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
	CLCNKA	NM_004070.4	MANE Select	c.868G>T	p.Gly290Cys	missense splice_region	Exon 10 of 20	NP_004061.3
	CLCNKA	NM_001042704.2		c.868G>T	p.Gly290Cys	missense splice_region	Exon 10 of 20	NP_001036169.1	P51800-3
	CLCNKA	NM_001257139.2		c.739G>T	p.Gly247Cys	missense splice_region	Exon 9 of 19	NP_001244068.1	P51800-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCNKA	ENST00000331433.5	TSL:1 MANE Select	c.868G>T	p.Gly290Cys	missense splice_region	Exon 10 of 20	ENSP00000332771.4	P51800-1
	CLCNKA	ENST00000375692.5	TSL:1	c.868G>T	p.Gly290Cys	missense splice_region	Exon 11 of 21	ENSP00000364844.1	P51800-3
	CLCNKA	ENST00000861487.1		c.868G>T	p.Gly290Cys	missense splice_region	Exon 10 of 20	ENSP00000531546.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461678 Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2 AN XY: 727160

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111910

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	0.46	N
PhyloP100		4.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.3	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.077	T
Polyphen		0.66	P
Vest4		0.21
MVP		0.87
MPC		0.60
ClinPred		0.56	D
GERP RS		2.3
Varity_R		0.18
gMVP		0.44
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0026
dbscSNV1_RF	Benign	0.048
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: rs1486642291; hg19: chr1-16354514;