NM_004070.4:c.247A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004070.4(CLCNKA):c.247A>G(p.Arg83Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 1,613,634 control chromosomes in the GnomAD database, including 257,855 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R83K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.59 ( 27334 hom., cov: 32)

Exomes 𝑓: 0.56 ( 230521 hom. )

Consequence

CLCNKA
NM_004070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.107

Publications

45 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=1.8806211E-6).

BP6

Variant 1-16024780-A-G is Benign according to our data. Variant chr1-16024780-A-G is described in ClinVar as Benign. ClinVar VariationId is 585697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4 link	c.247A>G	p.Arg83Gly	missense_variant	Exon 4 of 20	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.247A>G	p.Arg83Gly	missense_variant	Exon 4 of 20		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.229+852A>G		intron_variant	Intron 3 of 18		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5 link	c.247A>G	p.Arg83Gly	missense_variant	Exon 4 of 20	1	NM_004070.4	ENSP00000332771.4		P51800-1

Frequencies

GnomAD3 genomes

AF:

0.592

AC:

89861

AN:

151908

Hom.:

27307

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.381

Gnomad AMR

AF:

0.471

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.780

Gnomad SAS

AF:

0.571

Gnomad FIN

AF:

0.510

Gnomad MID

AF:

0.637

Gnomad NFE

AF:

0.560

Gnomad OTH

AF:

0.600

GnomAD2 exomes

AF:

0.551

AC:

138274

AN:

251076

AF XY:

0.553

show subpopulations

Gnomad AFR exome

AF:

0.705

Gnomad AMR exome

AF:

0.380

Gnomad ASJ exome

AF:

0.464

Gnomad EAS exome

AF:

0.757

Gnomad FIN exome

AF:

0.522

Gnomad NFE exome

AF:

0.560

Gnomad OTH exome

AF:

0.545

GnomAD4 exome

AF:

0.559

AC:

816601

AN:

1461608

Hom.:

230521

Cov.:

AF XY:

0.559

AC XY:

406144

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.714

AC:

23912

AN:

33472

American (AMR)

AF:

0.391

AC:

17478

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.467

AC:

12192

AN:

26124

East Asian (EAS)

AF:

0.737

AC:

29243

AN:

39696

South Asian (SAS)

AF:

0.551

AC:

47497

AN:

86252

European-Finnish (FIN)

AF:

0.522

AC:

27842

AN:

53322

Middle Eastern (MID)

AF:

0.550

AC:

3170

AN:

5764

European-Non Finnish (NFE)

AF:

0.558

AC:

620622

AN:

1111878

Other (OTH)

AF:

0.574

AC:

34645

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

20995

41991

62986

83982

104977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17456

34912

52368

69824

87280

<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

AF:

0.592

AC:

89927

AN:

152026

Hom.:

27334

Cov.:

AF XY:

0.584

AC XY:

43408

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.703

AC:

29171

AN:

41478

American (AMR)

AF:

0.470

AC:

7185

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1579

AN:

3468

East Asian (EAS)

AF:

0.780

AC:

4026

AN:

5162

South Asian (SAS)

AF:

0.571

AC:

2743

AN:

4806

European-Finnish (FIN)

AF:

0.510

AC:

5393

AN:

10572

Middle Eastern (MID)

AF:

0.637

AC:

186

AN:

292

European-Non Finnish (NFE)

AF:

0.560

AC:

38030

AN:

67950

Other (OTH)

AF:

0.599

AC:

1267

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1823

3646

5468

7291

9114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.569

Hom.:

10775

Bravo

AF:

0.591

TwinsUK

AF:

0.564

AC:

2092

ALSPAC

AF:

0.551

AC:

2124

ESP6500AA

AF:

0.696

AC:

3067

ESP6500EA

AF:

0.552

AC:

4748

ExAC

AF:

0.563

AC:

68366

Asia WGS

AF:

0.631

AC:

2195

AN:

3478

EpiCase

AF:

0.553

EpiControl

AF:

0.559

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23850580, 21248228) -

Bartter disease type 4B

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 16, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.0

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.086

.;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.0000019

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

L;L

PhyloP100

0.11

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.17

N;N

REVEL

Benign

0.23

Sift

Benign

0.39

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0

.;B

Vest4

0.095

MPC

0.45

ClinPred

0.0049

GERP RS

0.87

Varity_R

0.061

gMVP

0.33

Mutation Taster

=98/2

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over