1-16022642-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004070.4(CLCNKA):c.23G>A(p.Arg8His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,566,692 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 28 hom., cov: 33)

Exomes 𝑓: 0.020 ( 369 hom. )

Consequence

CLCNKA
NM_004070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.718

Publications

9 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041867197).

BP6

Variant 1-16022642-G-A is Benign according to our data. Variant chr1-16022642-G-A is described in ClinVar as [Benign]. Clinvar id is 1220926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0145 (2205/152276) while in subpopulation SAS AF = 0.0351 (169/4820). AF 95% confidence interval is 0.0307. There are 28 homozygotes in GnomAd4. There are 1051 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4 link	c.23G>A	p.Arg8His	missense_variant	Exon 2 of 20	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.23G>A	p.Arg8His	missense_variant	Exon 2 of 20		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.23G>A	p.Arg8His	missense_variant	Exon 2 of 19		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5 link	c.23G>A	p.Arg8His	missense_variant	Exon 2 of 20	1	NM_004070.4	ENSP00000332771.4		P51800-1

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2203

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00340

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00863

Gnomad ASJ

AF:

0.0392

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0348

Gnomad FIN

AF:

0.00876

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0216

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0158

AC:

2849

AN:

180034

AF XY:

0.0171

show subpopulations

Gnomad AFR exome

AF:

0.00202

Gnomad AMR exome

AF:

0.00664

Gnomad ASJ exome

AF:

0.0366

Gnomad EAS exome

AF:

0.0000725

Gnomad FIN exome

AF:

0.00748

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

AF:

0.0203

AC:

28661

AN:

1414416

Hom.:

369

Cov.:

AF XY:

0.0208

AC XY:

14566

AN XY:

699262

show subpopulations

African (AFR)

AF:

0.00317

AC:

104

AN:

32770

American (AMR)

AF:

0.00729

AC:

275

AN:

37724

Ashkenazi Jewish (ASJ)

AF:

0.0402

AC:

1000

AN:

24894

East Asian (EAS)

AF:

0.0000530

AC:

AN:

37718

South Asian (SAS)

AF:

0.0294

AC:

2334

AN:

79458

European-Finnish (FIN)

AF:

0.0101

AC:

510

AN:

50248

Middle Eastern (MID)

AF:

0.0300

AC:

170

AN:

5660

European-Non Finnish (NFE)

AF:

0.0213

AC:

23173

AN:

1087302

Other (OTH)

AF:

0.0186

AC:

1093

AN:

58642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

1380

2760

4141

5521

6901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0145

AC:

2205

AN:

152276

Hom.:

Cov.:

AF XY:

0.0141

AC XY:

1051

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00339

AC:

141

AN:

41562

American (AMR)

AF:

0.00862

AC:

132

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0392

AC:

136

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0351

AC:

169

AN:

4820

European-Finnish (FIN)

AF:

0.00876

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0216

AC:

1466

AN:

67996

Other (OTH)

AF:

0.0204

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

106

212

319

425

531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0200

Hom.:

Bravo

AF:

0.0139

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0210

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.0212

AC:

182

ExAC

AF:

0.0135

AC:

1608

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 07, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

.;.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Pathogenic

3.0

M;M;M

PhyloP100

0.72

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.027

D;D;D

Sift4G

Benign

0.065

T;T;T

Polyphen

0.25

.;.;B

Vest4

0.081

MPC

0.44

ClinPred

0.023

GERP RS

2.1

Varity_R

0.080

gMVP

0.29

Mutation Taster

=100/0

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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1-16022642-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over