Genetic Variant CLCNKA:p.Arg538His (chr1-16030665-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_004070.4(CLCNKA):c.1613G>A(p.Arg538His) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,460,906 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R538C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CLCNKA
NM_004070.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.60

Publications

4 publications found

Variant links:

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

CLCNKA links:

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ACMG classification

Classification was made for transcript

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 link	c.1613G>A	p.Arg538His	missense_variant	Exon 15 of 20	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.1613G>A	p.Arg538His	missense_variant	Exon 15 of 20		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.1484G>A	p.Arg495His	missense_variant	Exon 14 of 19		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCNKA	ENST00000331433.5 link	c.1613G>A	p.Arg538His	missense_variant	Exon 15 of 20	1	NM_004070.4	ENSP00000332771.4	P51800-1
CLCNKA	ENST00000375692.5 link	c.1613G>A	p.Arg538His	missense_variant	Exon 16 of 21	1		ENSP00000364844.1	P51800-3
CLCNKA	ENST00000439316.6 link	c.1484G>A	p.Arg495His	missense_variant	Exon 14 of 19	2		ENSP00000414445.2	P51800-2
CLCNKA	ENST00000464764.5 link	n.2217G>A		non_coding_transcript_exon_variant	Exon 19 of 24	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000280

AC:

AN:

249834

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460906

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112002

Other (OTH)

AF:

0.0000166

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.092

.;.;T

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.037

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

2.9

M;.;M

PhyloP100

6.6

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.77

N;N;N

REVEL

Uncertain

0.44

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.098

T;T;T

Polyphen

1.0

.;.;D

Vest4

0.58

MutPred

0.47

Gain of sheet (P = 0.0166);.;Gain of sheet (P = 0.0166);

MVP

0.86

MPC

0.85

ClinPred

0.86

GERP RS

3.9

Varity_R

0.094

gMVP

0.42

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over