1-16022585-G-A

Variant names:

• chr1-16022585-G-A
• rs3738637
• NM_004070.4:c.-7-28G>A

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.-7-28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0642 in 1,514,344 control chromosomes in the GnomAD database, including 3,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (334 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3336 hom.)
• Consequence: CLCNKA NM_004070.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.45
• Publications: 6 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: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-16022585-G-A is Benign according to our data. Variant chr1-16022585-G-A is described in ClinVar as [Benign]. Clinvar id is 1179730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.-7-28G>A		intron_variant	Intron 1 of 19	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.-7-28G>A		intron_variant	Intron 1 of 19		NP_001036169.1
CLCNKA	NM_001257139.2	c.-7-28G>A		intron_variant	Intron 1 of 18		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.-7-28G>A		intron_variant	Intron 1 of 19	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.0603 AC: 9178 AN: 152096 Hom.: 334 Cov.: 33

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0732

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.0961

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0604

Gnomad OTH AF: 0.0637

GnomAD2 exomes AF: 0.0715 AC: 10389 AN: 145232 AF XY: 0.0755

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.0784

Gnomad ASJ exome AF: 0.0537

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0593

Gnomad OTH exome AF: 0.0638

GnomAD4 exome AF: 0.0647 AC: 88105 AN: 1362130 Hom.: 3336 Cov.: 25 AF XY: 0.0668 AC XY: 44917 AN XY: 672490

African (AFR) AF: 0.0522 AC: 1628 AN: 31178

American (AMR) AF: 0.0770 AC: 2644 AN: 34340

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 1354 AN: 23816

East Asian (EAS) AF: 0.0649 AC: 2318 AN: 35728

South Asian (SAS) AF: 0.133 AC: 10147 AN: 76124

European-Finnish (FIN) AF: 0.0309 AC: 1493 AN: 48312

Middle Eastern (MID) AF: 0.0784 AC: 407 AN: 5190

European-Non Finnish (NFE) AF: 0.0612 AC: 64285 AN: 1050796

Other (OTH) AF: 0.0676 AC: 3829 AN: 56646

GnomAD4 genome AF: 0.0603 AC: 9182 AN: 152214 Hom.: 334 Cov.: 33 AF XY: 0.0606 AC XY: 4513 AN XY: 74416

African (AFR) AF: 0.0500 AC: 2078 AN: 41542

American (AMR) AF: 0.0731 AC: 1119 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 188 AN: 3472

East Asian (EAS) AF: 0.0954 AC: 493 AN: 5170

South Asian (SAS) AF: 0.145 AC: 698 AN: 4820

European-Finnish (FIN) AF: 0.0296 AC: 314 AN: 10608

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0604 AC: 4106 AN: 67988

Other (OTH) AF: 0.0635 AC: 134 AN: 2110

Alfa AF: 0.0581 Hom.: 57

Bravo AF: 0.0611

Asia WGS AF: 0.122 AC: 423 AN: 3478

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

- -

Dec 26, 2019

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	-0.88
CADD	Benign	0.44
DANN	Benign	0.77
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3738637; hg19: chr1-16349080; COSMIC: COSV58891943; COSMIC: COSV58891943;