1-16033649-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004070.4(CLCNKA):c.2055T>C(p.Ala685Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00895 in 121,428 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 7 hom., cov: 21)

Exomes 𝑓: 0.0040 ( 38 hom. )

Failed GnomAD Quality Control

Consequence

CLCNKA
NM_004070.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.574

Publications

2 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 1-16033649-T-C is Benign according to our data. Variant chr1-16033649-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.574 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 7 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CLCNKA	NM_004070.4 link	c.2055T>C	p.Ala685Ala	synonymous_variant	Exon 20 of 20	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2 link	c.2052T>C	p.Ala684Ala	synonymous_variant	Exon 20 of 20		NP_001036169.1
CLCNKA	NM_001257139.2 link	c.1926T>C	p.Ala642Ala	synonymous_variant	Exon 19 of 19		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CLCNKA	ENST00000331433.5 link	c.2055T>C	p.Ala685Ala	synonymous_variant	Exon 20 of 20	1	NM_004070.4	ENSP00000332771.4
CLCNKA	ENST00000375692.5 link	c.2052T>C	p.Ala684Ala	synonymous_variant	Exon 21 of 21	1		ENSP00000364844.1
CLCNKA	ENST00000439316.6 link	c.1926T>C	p.Ala642Ala	synonymous_variant	Exon 19 of 19	2		ENSP00000414445.2
CLCNKA	ENST00000464764.5 link	n.2659T>C		non_coding_transcript_exon_variant	Exon 24 of 24	2

Frequencies

GnomAD3 genomes

AF:

0.00893

AC:

1084

AN:

121380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00515

Gnomad ASJ

AF:

0.00787

Gnomad EAS

AF:

0.000547

Gnomad SAS

AF:

0.00656

Gnomad FIN

AF:

0.0317

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00729

Gnomad OTH

AF:

0.00731

GnomAD2 exomes

AF:

0.00681

AC:

1541

AN:

226374

AF XY:

0.00681

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.00384

Gnomad ASJ exome

AF:

0.00478

Gnomad EAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.0147

Gnomad NFE exome

AF:

0.00799

Gnomad OTH exome

AF:

0.00654

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00401

AC:

5234

AN:

1303772

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

2680

AN XY:

647268

show subpopulations

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

African (AFR)

AF:

0.00565

AC:

167

AN:

29582

American (AMR)

AF:

0.00217

AC:

AN:

39598

Ashkenazi Jewish (ASJ)

AF:

0.00558

AC:

111

AN:

19888

East Asian (EAS)

AF:

0.00215

AC:

AN:

23704

South Asian (SAS)

AF:

0.00384

AC:

324

AN:

84306

European-Finnish (FIN)

AF:

0.0226

AC:

952

AN:

42158

Middle Eastern (MID)

AF:

0.00492

AC:

AN:

4876

European-Non Finnish (NFE)

AF:

0.00324

AC:

3267

AN:

1009276

Other (OTH)

AF:

0.00500

AC:

252

AN:

50384

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

Heterozygous variant carriers

239

479

718

958

1197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00895

AC:

1087

AN:

121428

Hom.:

Cov.:

AF XY:

0.00997

AC XY:

564

AN XY:

56586

show subpopulations

African (AFR)

AF:

0.0109

AC:

344

AN:

31494

American (AMR)

AF:

0.00514

AC:

AN:

9532

Ashkenazi Jewish (ASJ)

AF:

0.00787

AC:

AN:

3176

East Asian (EAS)

AF:

0.000547

AC:

AN:

3656

South Asian (SAS)

AF:

0.00658

AC:

AN:

3496

European-Finnish (FIN)

AF:

0.0317

AC:

182

AN:

5734

Middle Eastern (MID)

AF:

0.00

AC:

AN:

176

European-Non Finnish (NFE)

AF:

0.00730

AC:

450

AN:

61684

Other (OTH)

AF:

0.00727

AC:

AN:

1650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00849

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 26, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLCNKA: BP4, BP7 -

not specified

Benign:1

Apr 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

6.1

(source)

DANN

Benign

0.55

PhyloP100

-0.57

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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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