1-16023055-G-T

Variant names:

• chr1-16023055-G-T
• rs111470804
• NM_004070.4:c.100+336G>T

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+336G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 152,368 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.021 (59 hom., cov: 34)
• Consequence: CLCNKA NM_004070.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.325
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-16023055-G-T is Benign according to our data. Variant chr1-16023055-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1316530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0214 (3260/152368) while in subpopulation NFE AF = 0.0284 (1933/68028). AF 95% confidence interval is 0.0274. There are 59 homozygotes in GnomAd4. There are 1630 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.100+336G>T		intron_variant	Intron 2 of 19	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.100+336G>T		intron_variant	Intron 2 of 19		NP_001036169.1
CLCNKA	NM_001257139.2	c.100+336G>T		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+336G>T		intron_variant	Intron 2 of 19	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3259 AN: 152250 Hom.: 59 Cov.: 34

Gnomad AFR AF: 0.00506

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0619

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0368

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0235

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

GnomAD4 genome AF: 0.0214 AC: 3260 AN: 152368 Hom.: 59 Cov.: 34 AF XY: 0.0219 AC XY: 1630 AN XY: 74510

African (AFR) AF: 0.00507 AC: 211 AN: 41590

American (AMR) AF: 0.0167 AC: 256 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0619 AC: 215 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4832

European-Finnish (FIN) AF: 0.0368 AC: 391 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0284 AC: 1933 AN: 68028

Other (OTH) AF: 0.0232 AC: 49 AN: 2110

Alfa AF: 0.0130 Hom.: 3

Bravo AF: 0.0195

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

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	2.0
DANN	Benign	0.51
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism

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: rs111470804; hg19: chr1-16349550;