chr1-16022959-T-C

Variant names:

• chr1-16022959-T-C
• rs111821117
• NM_004070.4:c.100+240T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004070.4(CLCNKA):​c.100+240T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 152,324 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.011 (11 hom., cov: 33)
• Consequence: CLCNKA NM_004070.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.02
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-16022959-T-C is Benign according to our data. Variant chr1-16022959-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1318226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0112 (1713/152324) while in subpopulation SAS AF = 0.0363 (175/4818). AF 95% confidence interval is 0.0319. There are 11 homozygotes in GnomAd4. There are 853 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.100+240T>C		intron_variant	Intron 2 of 19	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.100+240T>C		intron_variant	Intron 2 of 19		NP_001036169.1
CLCNKA	NM_001257139.2	c.100+240T>C		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.100+240T>C		intron_variant	Intron 2 of 19	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1709 AN: 152206 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0359

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0110

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

GnomAD4 genome AF: 0.0112 AC: 1713 AN: 152324 Hom.: 11 Cov.: 33 AF XY: 0.0115 AC XY: 853 AN XY: 74484

African (AFR) AF: 0.00274 AC: 114 AN: 41580

American (AMR) AF: 0.00614 AC: 94 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4818

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10628

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1113 AN: 68022

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0129 Hom.: 1

Bravo AF: 0.0102

Asia WGS AF: 0.0100 AC: 36 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 13, 2020

GeneDx

Significance: Likely 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	-0.91
CADD	Benign	0.47
DANN	Benign	0.64
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs111821117; hg19: chr1-16349454;