Genetic Variant CLCNKA:c.-82T>C (chr1-16021917-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000375692.5(CLCNKA):c.-82T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,618 control chromosomes in the GnomAD database, including 38,088 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.70 ( 37935 hom., cov: 33)

Exomes 𝑓: 0.75 ( 153 hom. )

Consequence

CLCNKA
ENST00000375692.5 splice_region

Scores

Splicing: ADA: 0.00007013

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.53

Publications

17 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
CLCNKA	NM_004070.4 link	c.-154T>C	upstream_gene_variant	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.-154T>C	upstream_gene_variant		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.-154T>C	upstream_gene_variant		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5 link	c.-154T>C		upstream_gene_variant		1	NM_004070.4	ENSP00000332771.4		P51800-1

Frequencies

GnomAD3 genomes

AF:

0.703

AC:

106851

AN:

151972

Hom.:

37913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.739

Gnomad AMI

AF:

0.569

Gnomad AMR

AF:

0.644

Gnomad ASJ

AF:

0.606

Gnomad EAS

AF:

0.975

Gnomad SAS

AF:

0.641

Gnomad FIN

AF:

0.729

Gnomad MID

AF:

0.699

Gnomad NFE

AF:

0.681

Gnomad OTH

AF:

0.714

GnomAD4 exome

AF:

0.752

AC:

397

AN:

528

Hom.:

153

Cov.:

AF XY:

0.751

AC XY:

314

AN XY:

418

show subpopulations

African (AFR)

AF:

0.889

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.950

AC:

AN:

South Asian (SAS)

AF:

0.750

AC:

AN:

European-Finnish (FIN)

AF:

0.917

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.741

AC:

323

AN:

436

Other (OTH)

AF:

0.633

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

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

AF:

0.703

AC:

106923

AN:

152090

Hom.:

37935

Cov.:

AF XY:

0.702

AC XY:

52214

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.739

AC:

30662

AN:

41500

American (AMR)

AF:

0.643

AC:

9830

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.606

AC:

2102

AN:

3466

East Asian (EAS)

AF:

0.974

AC:

5035

AN:

5168

South Asian (SAS)

AF:

0.640

AC:

3081

AN:

4816

European-Finnish (FIN)

AF:

0.729

AC:

7699

AN:

10566

Middle Eastern (MID)

AF:

0.697

AC:

205

AN:

294

European-Non Finnish (NFE)

AF:

0.681

AC:

46290

AN:

67980

Other (OTH)

AF:

0.713

AC:

1500

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1612

3223

4835

6446

8058

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.684

Hom.:

133958

Bravo

AF:

0.698

Asia WGS

AF:

0.792

AC:

2752

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.79

(source)

DANN

Benign

0.41

PhyloP100

-1.5

PromoterAI

-0.034

Neutral

(source)

Mutation Taster

=252/48

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000070

dbscSNV1_RF

Benign

0.0020

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

Computational scores

Splicing

Publications

Other links and lift over