1-16023628-C-G

Variant names:

• chr1-16023628-C-G
• rs2017577
• NM_004070.4:c.101-172C>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.101-172C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 152,060 control chromosomes in the GnomAD database, including 27,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.59 (27345 hom., cov: 32)
• Consequence: CLCNKA NM_004070.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.497
• Publications: 4 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=-1.0).
• BP6: Variant 1-16023628-C-G is Benign according to our data. Variant chr1-16023628-C-G is described in ClinVar as [Benign]. Clinvar id is 1250545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.101-172C>G		intron_variant	Intron 2 of 19	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.101-172C>G		intron_variant	Intron 2 of 19		NP_001036169.1
CLCNKA	NM_001257139.2	c.101-172C>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.101-172C>G		intron_variant	Intron 2 of 19	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89938 AN: 151942 Hom.: 27318 Cov.: 32

Gnomad AFR AF: 0.703

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.511

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.601

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.592 AC: 90004 AN: 152060 Hom.: 27345 Cov.: 32 AF XY: 0.585 AC XY: 43453 AN XY: 74324

African (AFR) AF: 0.703 AC: 29185 AN: 41498

American (AMR) AF: 0.471 AC: 7206 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1597 AN: 3468

East Asian (EAS) AF: 0.779 AC: 4018 AN: 5158

South Asian (SAS) AF: 0.571 AC: 2748 AN: 4816

European-Finnish (FIN) AF: 0.511 AC: 5402 AN: 10574

Middle Eastern (MID) AF: 0.634 AC: 185 AN: 292

European-Non Finnish (NFE) AF: 0.560 AC: 38052 AN: 67942

Other (OTH) AF: 0.599 AC: 1266 AN: 2112

Alfa AF: 0.576 Hom.: 3028

Bravo AF: 0.591

Asia WGS AF: 0.632 AC: 2198 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

- -

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	-1.0
CADD	Benign	0.19
DANN	Benign	0.55
PhyloP100		-0.50
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: rs2017577; hg19: chr1-16350123; COSMIC: COSV58890901; COSMIC: COSV58890901;