1-16023767-A-G

Variant names:

• chr1-16023767-A-G
• rs1537803
• NM_004070.4:c.101-33A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.589
• Publications: 1 publications found

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

ACMG classification

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.101-33A>G		intron_variant	Intron 2 of 19	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.101-33A>G		intron_variant	Intron 2 of 19		NP_001036169.1
CLCNKA	NM_001257139.2	c.101-33A>G		intron_variant	Intron 2 of 18		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.101-33A>G		intron_variant	Intron 2 of 19	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.0886 AC: 13471 AN: 152118 Hom.: 688 Cov.: 33

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

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.: 32 AF XY: 0.0901 AC XY: 65430 AN XY: 726418

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

GnomAD4 genome AF: 0.0886 AC: 13490 AN: 152236 Hom.: 692 Cov.: 33 AF XY: 0.0859 AC XY: 6398 AN XY: 74442

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: 22 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: 23 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6941 AN: 68010

Other (OTH) AF: 0.0770 AC: 163 AN: 2116

Alfa AF: 0.0945 Hom.: 169

Bravo AF: 0.0830

Asia WGS AF: 0.0350 AC: 123 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

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	-0.90
CADD	Benign	0.52
DANN	Benign	0.45
PhyloP100		-0.59
BranchPoint Hunter		0.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1537803; hg19: chr1-16350262; COSMIC: COSV58894803; COSMIC: COSV58894803;