1-16030006-G-C

Variant names:

• chr1-16030006-G-C
• rs1805152
• NM_004070.4:c.1339G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004070.4(CLCNKA):​c.1339G>C​(p.Ala447Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A447T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCNKA NM_004070.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• Publications: 45 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.1339G>C	p.Ala447Pro	missense_variant	Exon 14 of 20	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.1339G>C	p.Ala447Pro	missense_variant	Exon 14 of 20		NP_001036169.1
CLCNKA	NM_001257139.2	c.1210G>C	p.Ala404Pro	missense_variant	Exon 13 of 19		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.1339G>C	p.Ala447Pro	missense_variant	Exon 14 of 20	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250078 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 41302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0	.;.;D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.083	N
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.5	M;.;M
PhyloP100		-0.32
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.028	D;D;D
Sift4G	Benign	0.14	T;T;T
Vest4		0.65
ClinPred		0.29	T
GERP RS		0.33
Varity_R		0.57
gMVP		0.73
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -41

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

Other links and lift over

dbSNP: rs1805152; hg19: chr1-16356501;