NM_004070.4:c.92C>A

Variant names:

• chr1-16022711-C-A
• rs866781116
• NM_004070.4:c.92C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004070.4(CLCNKA):​c.92C>A​(p.Ala31Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. A31G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CLCNKA NM_004070.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.619
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05417639).

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.92C>A	p.Ala31Asp	missense	Exon 2 of 20	NP_004061.3
	CLCNKA	NM_001042704.2		c.92C>A	p.Ala31Asp	missense	Exon 2 of 20	NP_001036169.1	P51800-3
	CLCNKA	NM_001257139.2		c.92C>A	p.Ala31Asp	missense	Exon 2 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.92C>A	p.Ala31Asp	missense	Exon 2 of 20	ENSP00000332771.4	P51800-1
	CLCNKA	ENST00000375692.5	TSL:1	c.92C>A	p.Ala31Asp	missense	Exon 3 of 21	ENSP00000364844.1	P51800-3
	CLCNKA	ENST00000861487.1		c.92C>A	p.Ala31Asp	missense	Exon 2 of 20	ENSP00000531546.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383668 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 681618

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

African (AFR) AF: 0.00 AC: 0 AN: 31824

American (AMR) AF: 0.00 AC: 0 AN: 34490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23458

East Asian (EAS) AF: 0.00 AC: 0 AN: 36428

South Asian (SAS) AF: 0.00 AC: 0 AN: 74820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1071068

Other (OTH) AF: 0.00 AC: 0 AN: 57352

⚠️ 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 Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.0
DANN	Benign	0.66
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.62
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.20
Sift	Benign	0.55	T
Sift4G	Benign	0.63	T
Polyphen		0.0050	B
Vest4		0.064
MutPred		0.43		Loss of MoRF binding (P = 0.0436)
MVP		0.38
MPC		0.53
ClinPred		0.52	D
GERP RS		2.2
Varity_R		0.059
gMVP		0.20
Mutation Taster		=96/4	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: rs866781116; hg19: chr1-16349206;