rs1805152

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1339G>A(p.Ala447Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,588,384 control chromosomes in the GnomAD database, including 254,002 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 (★★).

Frequency

Genomes: 𝑓 0.59 ( 27511 hom., cov: 32)

Exomes 𝑓: 0.55 ( 226491 hom. )

Consequence

CLCNKA
NM_004070.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.320

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=3.136834E-6).

BP6

Variant 1-16030006-G-A is Benign according to our data. Variant chr1-16030006-G-A is described in ClinVar as Benign. ClinVar VariationId is 1177821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCNKA	NM_004070.4	MANE Select	c.1339G>A	p.Ala447Thr	missense	Exon 14 of 20	NP_004061.3
CLCNKA	NM_001042704.2		c.1339G>A	p.Ala447Thr	missense	Exon 14 of 20	NP_001036169.1
CLCNKA	NM_001257139.2		c.1210G>A	p.Ala404Thr	missense	Exon 13 of 19	NP_001244068.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLCNKA	ENST00000331433.5	TSL:1 MANE Select	c.1339G>A	p.Ala447Thr	missense	Exon 14 of 20	ENSP00000332771.4
CLCNKA	ENST00000375692.5	TSL:1	c.1339G>A	p.Ala447Thr	missense	Exon 15 of 21	ENSP00000364844.1
CLCNKA	ENST00000861487.1		c.1378G>A	p.Ala460Thr	missense	Exon 14 of 20	ENSP00000531546.1

Frequencies

GnomAD3 genomes

AF:

0.593

AC:

89998

AN:

151850

Hom.:

27483

Cov.:

show subpopulations

Gnomad AFR

AF:

0.720

Gnomad AMI

AF:

0.378

Gnomad AMR

AF:

0.469

Gnomad ASJ

AF:

0.446

Gnomad EAS

AF:

0.778

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.506

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.594

GnomAD2 exomes

AF:

0.548

AC:

136942

AN:

250078

AF XY:

0.549

show subpopulations

Gnomad AFR exome

AF:

0.721

Gnomad AMR exome

AF:

0.378

Gnomad ASJ exome

AF:

0.450

Gnomad EAS exome

AF:

0.756

Gnomad FIN exome

AF:

0.519

Gnomad NFE exome

AF:

0.555

Gnomad OTH exome

AF:

0.539

GnomAD4 exome

AF:

0.553

AC:

795047

AN:

1436416

Hom.:

226491

Cov.:

AF XY:

0.553

AC XY:

395978

AN XY:

715580

show subpopulations

African (AFR)

AF:

0.735

AC:

24446

AN:

33246

American (AMR)

AF:

0.388

AC:

17341

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.452

AC:

11773

AN:

26038

East Asian (EAS)

AF:

0.735

AC:

29182

AN:

39698

South Asian (SAS)

AF:

0.545

AC:

46904

AN:

86028

European-Finnish (FIN)

AF:

0.520

AC:

27466

AN:

52832

Middle Eastern (MID)

AF:

0.534

AC:

3058

AN:

5730

European-Non Finnish (NFE)

AF:

0.552

AC:

600934

AN:

1088542

Other (OTH)

AF:

0.569

AC:

33943

AN:

59620

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

16391

32782

49172

65563

81954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16644

33288

49932

66576

83220

<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:

0.593

AC:

90063

AN:

151968

Hom.:

27511

Cov.:

AF XY:

0.585

AC XY:

43451

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.720

AC:

29855

AN:

41456

American (AMR)

AF:

0.468

AC:

7163

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.446

AC:

1545

AN:

3464

East Asian (EAS)

AF:

0.777

AC:

3996

AN:

5140

South Asian (SAS)

AF:

0.568

AC:

2735

AN:

4818

European-Finnish (FIN)

AF:

0.506

AC:

5348

AN:

10574

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.554

AC:

37642

AN:

67906

Other (OTH)

AF:

0.592

AC:

1250

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1794

3588

5381

7175

8969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

740

1480

2220

2960

3700

<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:

0.555

Hom.:

41302

Bravo

AF:

0.592

TwinsUK

AF:

0.548

AC:

2033

ALSPAC

AF:

0.544

AC:

2098

ESP6500AA

AF:

0.713

AC:

3140

ESP6500EA

AF:

0.544

AC:

4681

ExAC

AF:

0.560

AC:

68019

Asia WGS

AF:

0.630

AC:

2188

AN:

3478

EpiCase

AF:

0.546

EpiControl

AF:

0.552

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Bartter disease type 4B (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.1

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.30

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0000031

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

PhyloP100

-0.32

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.10

REVEL

Benign

0.17

Sift

Benign

0.12

Sift4G

Benign

0.30

Polyphen

0.0020

Vest4

0.029

MPC

0.23

ClinPred

0.0056

GERP RS

0.33

Varity_R

0.048

gMVP

0.33

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over