1-16030665-G-C

Variant names:

• chr1-16030665-G-C
• rs762119830
• NM_004070.4:c.1613G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004070.4(CLCNKA):​c.1613G>C​(p.Arg538Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R538C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLCNKA NM_004070.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60
• Publications: 4 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: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, G2P
• Bartter syndrome type 4

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.1613G>C	p.Arg538Pro	missense_variant	Exon 15 of 20	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.1613G>C	p.Arg538Pro	missense_variant	Exon 15 of 20		NP_001036169.1
CLCNKA	NM_001257139.2	c.1484G>C	p.Arg495Pro	missense_variant	Exon 14 of 19		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.1613G>C	p.Arg538Pro	missense_variant	Exon 15 of 20	1	NM_004070.4	ENSP00000332771.4
CLCNKA	ENST00000375692.5	c.1613G>C	p.Arg538Pro	missense_variant	Exon 16 of 21	1		ENSP00000364844.1
CLCNKA	ENST00000439316.6	c.1484G>C	p.Arg495Pro	missense_variant	Exon 14 of 19	2		ENSP00000414445.2
CLCNKA	ENST00000464764.5	n.2217G>C		non_coding_transcript_exon_variant	Exon 19 of 24	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bartter disease type 4B Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.16	.;.;T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	2.9	M;.;M
PhyloP100		6.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N;D;N
REVEL	Uncertain	0.52
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	.;.;D
Vest4		0.75
MutPred		0.50		Loss of MoRF binding (P = 0.007);.;Loss of MoRF binding (P = 0.007);
MVP		0.80
MPC		0.95
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.45
gMVP		0.65
Mutation Taster		=75/25	polymorphism

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: rs762119830; hg19: chr1-16357160;