Genetic Variant CLCNKA:c.101-33A>G (chr1-16023767-A-G) – ACMG Classification: Benign (-20 pts)

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.101-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0915 in 1,612,362 control chromosomes in the GnomAD database, including 7,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.089 ( 692 hom., cov: 33)

Exomes 𝑓: 0.092 ( 6756 hom. )

Consequence

CLCNKA
NM_004070.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.589

Publications

1 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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics
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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-16023767-A-G is Benign according to our data. Variant chr1-16023767-A-G is described in ClinVar as Benign. ClinVar VariationId is 1222414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 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	Effect	Exon Rank	Protein	UniProt
CLCNKA	NM_004070.4	MANE Select	c.101-33A>G	intron	N/A	NP_004061.3
CLCNKA	NM_001042704.2		c.101-33A>G	intron	N/A	NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2		c.101-33A>G	intron	N/A	NP_001244068.1	P51800-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLCNKA	ENST00000331433.5	TSL:1 MANE Select	c.101-33A>G	intron	N/A	ENSP00000332771.4	P51800-1
CLCNKA	ENST00000375692.5	TSL:1	c.101-33A>G	intron	N/A	ENSP00000364844.1	P51800-3
CLCNKA	ENST00000861487.1		c.101-33A>G	intron	N/A	ENSP00000531546.1

Frequencies

GnomAD3 genomes

AF:

0.0886

AC:

13471

AN:

152118

Hom.:

688

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0898

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0629

Gnomad ASJ

AF:

0.0426

Gnomad EAS

AF:

0.00424

Gnomad SAS

AF:

0.0422

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0783

GnomAD2 exomes

AF:

0.0760

AC:

19040

AN:

250544

AF XY:

0.0754

show subpopulations

Gnomad AFR exome

AF:

0.0897

Gnomad AMR exome

AF:

0.0383

Gnomad ASJ exome

AF:

0.0355

Gnomad EAS exome

AF:

0.00239

Gnomad FIN exome

AF:

0.129

Gnomad NFE exome

AF:

0.0994

Gnomad OTH exome

AF:

0.0798

GnomAD4 exome

AF:

0.0918

AC:

134007

AN:

1460126

Hom.:

6756

Cov.:

AF XY:

0.0901

AC XY:

65430

AN XY:

726418

show subpopulations

African (AFR)

AF:

0.0915

AC:

3058

AN:

33410

American (AMR)

AF:

0.0405

AC:

1807

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0402

AC:

1049

AN:

26102

East Asian (EAS)

AF:

0.00696

AC:

276

AN:

39662

South Asian (SAS)

AF:

0.0434

AC:

3740

AN:

86220

European-Finnish (FIN)

AF:

0.125

AC:

6629

AN:

53212

Middle Eastern (MID)

AF:

0.0470

AC:

271

AN:

5762

European-Non Finnish (NFE)

AF:

0.101

AC:

111999

AN:

1110772

Other (OTH)

AF:

0.0859

AC:

5178

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

5924

11848

17772

23696

29620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3982

7964

11946

15928

19910

<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:

0.0886

AC:

13490

AN:

152236

Hom.:

692

Cov.:

AF XY:

0.0859

AC XY:

6398

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0900

AC:

3739

AN:

41528

American (AMR)

AF:

0.0628

AC:

961

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0426

AC:

148

AN:

3472

East Asian (EAS)

AF:

0.00425

AC:

AN:

5176

South Asian (SAS)

AF:

0.0423

AC:

204

AN:

4828

European-Finnish (FIN)

AF:

0.119

AC:

1265

AN:

10602

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6941

AN:

68010

Other (OTH)

AF:

0.0770

AC:

163

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

624

1248

1872

2496

3120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0945

Hom.:

169

Bravo

AF:

0.0830

Asia WGS

AF:

0.0350

AC:

123

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.52

(source)

DANN

Benign

0.45

PhyloP100

-0.59

BranchPoint Hunter

0.0

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over