1-16022965-T-C

Variant names:

• chr1-16022965-T-C
• rs9442214
• NM_004070.4:c.100+246T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004070.4(CLCNKA):​c.100+246T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 152,196 control chromosomes in the GnomAD database, including 37,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.70 (37633 hom., cov: 34)
• Consequence: CLCNKA NM_004070.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0700
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-16022965-T-C is Benign according to our data. Variant chr1-16022965-T-C is described in ClinVar as [Benign]. Clinvar id is 1291597.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.100+246T>C		intron_variant	Intron 2 of 19	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.100+246T>C		intron_variant	Intron 2 of 19		NP_001036169.1
CLCNKA	NM_001257139.2	c.100+246T>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+246T>C		intron_variant	Intron 2 of 19	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106428 AN: 152078 Hom.: 37608 Cov.: 34

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.975

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.713

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

GnomAD4 genome AF: 0.700 AC: 106504 AN: 152196 Hom.: 37633 Cov.: 34 AF XY: 0.699 AC XY: 51974 AN XY: 74396

African (AFR) AF: 0.741 AC: 30784 AN: 41534

American (AMR) AF: 0.643 AC: 9827 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 2082 AN: 3470

East Asian (EAS) AF: 0.974 AC: 5051 AN: 5184

South Asian (SAS) AF: 0.640 AC: 3089 AN: 4824

European-Finnish (FIN) AF: 0.710 AC: 7526 AN: 10594

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45910 AN: 67982

Other (OTH) AF: 0.712 AC: 1505 AN: 2114

Alfa AF: 0.689 Hom.: 4247

Bravo AF: 0.697

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.4
DANN	Benign	0.60
PhyloP100		0.070
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: rs9442214; hg19: chr1-16349460;