1-16032437-T-C

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.1846-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,608,830 control chromosomes in the GnomAD database, including 372,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37830 hom., cov: 33)

Exomes 𝑓: 0.67 ( 334827 hom. )

Consequence

CLCNKA
NM_004070.4 splice_region, intron

Scores

Splicing: ADA: 0.00005001

Clinical Significance

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

Conservation

PhyloP100: -0.0590

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 1-16032437-T-C is Benign according to our data. Variant chr1-16032437-T-C is described in ClinVar as [Benign]. Clinvar id is 585696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4 link	c.1846-6T>C	splice_region_variant, intron_variant	Intron 17 of 19	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.1846-9T>C	intron_variant	Intron 17 of 19		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.1717-6T>C	splice_region_variant, intron_variant	Intron 16 of 18		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCNKA	ENST00000331433.5 link	c.1846-6T>C	splice_region_variant, intron_variant	Intron 17 of 19	1	NM_004070.4	ENSP00000332771.4	P51800-1
CLCNKA	ENST00000375692.5 link	c.1846-9T>C	intron_variant	Intron 18 of 20	1		ENSP00000364844.1	P51800-3
CLCNKA	ENST00000439316.6 link	c.1717-6T>C	splice_region_variant, intron_variant	Intron 16 of 18	2		ENSP00000414445.2	P51800-2
CLCNKA	ENST00000464764.5 link	n.2450-6T>C	splice_region_variant, intron_variant	Intron 21 of 23	2

Frequencies

GnomAD3 genomes

AF:

0.701

AC:

106598

AN:

152028

Hom.:

37803

Cov.:

show subpopulations

Gnomad AFR

AF:

0.761

Gnomad AMI

AF:

0.567

Gnomad AMR

AF:

0.634

Gnomad ASJ

AF:

0.589

Gnomad EAS

AF:

0.975

Gnomad SAS

AF:

0.637

Gnomad FIN

AF:

0.706

Gnomad MID

AF:

0.718

Gnomad NFE

AF:

0.670

Gnomad OTH

AF:

0.705

GnomAD2 exomes

AF:

0.682

AC:

171024

AN:

250740

AF XY:

0.678

show subpopulations

Gnomad AFR exome

AF:

0.764

Gnomad AMR exome

AF:

0.597

Gnomad ASJ exome

AF:

0.585

Gnomad EAS exome

AF:

0.971

Gnomad FIN exome

AF:

0.712

Gnomad NFE exome

AF:

0.670

Gnomad OTH exome

AF:

0.667

GnomAD4 exome

AF:

0.675

AC:

983127

AN:

1456684

Hom.:

334827

Cov.:

AF XY:

0.673

AC XY:

487813

AN XY:

724878

show subpopulations

African (AFR)

AF:

0.773

AC:

25829

AN:

33426

American (AMR)

AF:

0.603

AC:

26959

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.585

AC:

15267

AN:

26078

East Asian (EAS)

AF:

0.982

AC:

38977

AN:

39684

South Asian (SAS)

AF:

0.615

AC:

53005

AN:

86174

European-Finnish (FIN)

AF:

0.716

AC:

37648

AN:

52550

Middle Eastern (MID)

AF:

0.629

AC:

3617

AN:

5754

European-Non Finnish (NFE)

AF:

0.668

AC:

740608

AN:

1108076

Other (OTH)

AF:

0.684

AC:

41217

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

16408

32816

49224

65632

82040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.701

AC:

106675

AN:

152146

Hom.:

37830

Cov.:

AF XY:

0.699

AC XY:

52020

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.762

AC:

31612

AN:

41508

American (AMR)

AF:

0.634

AC:

9689

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

2045

AN:

3472

East Asian (EAS)

AF:

0.975

AC:

5050

AN:

5182

South Asian (SAS)

AF:

0.636

AC:

3069

AN:

4824

European-Finnish (FIN)

AF:

0.706

AC:

7480

AN:

10598

Middle Eastern (MID)

AF:

0.718

AC:

211

AN:

294

European-Non Finnish (NFE)

AF:

0.670

AC:

45520

AN:

67964

Other (OTH)

AF:

0.705

AC:

1484

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1606

3212

4819

6425

8031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.661

Hom.:

12693

Bravo

AF:

0.698

Asia WGS

AF:

0.791

AC:

2750

AN:

3478

EpiCase

AF:

0.655

EpiControl

AF:

0.662

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 06, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bartter disease type 4B

Benign:1

Jul 22, 2021

Genome-Nilou Lab

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

-0.94

CADD

Benign

1.9

(source)

DANN

Benign

0.67

PhyloP100

-0.059

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000050

dbscSNV1_RF

Benign

0.020

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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1-16032437-T-C

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