Genetic Variant CLCNKA:c.1227+10delC (chr1-16029304-GC-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_004070.4(CLCNKA):c.1227+10delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00669 in 152,248 control chromosomes in the GnomAD database, including 20 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0067 ( 20 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

CLCNKA
NM_004070.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.25

Publications

0 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 -10 ACMG points.

BP6

Variant 1-16029304-GC-G is Benign according to our data. Variant chr1-16029304-GC-G is described in ClinVar as [Benign]. Clinvar id is 447083.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00669 (1018/152248) while in subpopulation AFR AF = 0.0232 (964/41548). AF 95% confidence interval is 0.022. There are 20 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4 link	c.1227+10delC	intron_variant	Intron 12 of 19	ENST00000331433.5	NP_004061.3	P51800-1
CLCNKA	NM_001042704.2 link	c.1227+10delC	intron_variant	Intron 12 of 19		NP_001036169.1	P51800-3
CLCNKA	NM_001257139.2 link	c.1098+10delC	intron_variant	Intron 11 of 18		NP_001244068.1	P51800-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5 link	c.1227+6delC		splice_region_variant, intron_variant	Intron 12 of 19	1	NM_004070.4	ENSP00000332771.4		P51800-1

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

1018

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00172

AC:

431

AN:

250816

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.0240

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000971

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000690

AC:

1008

AN:

1461450

Hom.:

Cov.:

AF XY:

0.000600

AC XY:

436

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.0231

AC:

773

AN:

33476

American (AMR)

AF:

0.000783

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53050

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000899

AC:

100

AN:

1111976

Other (OTH)

AF:

0.00154

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00669

AC:

1018

AN:

152248

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

463

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0232

AC:

964

AN:

41548

American (AMR)

AF:

0.00268

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67998

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

138

184

230

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:

0.000306

Hom.:

Bravo

AF:

0.00749

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 20, 2016

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

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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