1-16029304-GC-G

Variant names:

• chr1-16029304-GC-G
• rs58210748
• NM_004070.4:c.1227+10delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004070.4(CLCNKA):​c.1227+10delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00669 in 152,248 control chromosomes in the GnomAD database, including 20 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCNKA NM_004070.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.25
• 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 -10 ACMG points.

• BP6: Variant 1-16029304-GC-G is Benign according to our data. Variant chr1-16029304-GC-G is described in ClinVar as [Benign]. Clinvar id is 447083.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00669 (1018/152248) while in subpopulation AFR AF = 0.0232 (964/41548). AF 95% confidence interval is 0.022. There are 20 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCNKA	NM_004070.4	c.1227+10delC		intron_variant	Intron 12 of 19	ENST00000331433.5	NP_004061.3
CLCNKA	NM_001042704.2	c.1227+10delC		intron_variant	Intron 12 of 19		NP_001036169.1
CLCNKA	NM_001257139.2	c.1098+10delC		intron_variant	Intron 11 of 18		NP_001244068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCNKA	ENST00000331433.5	c.1227+6delC		splice_region_variant, intron_variant	Intron 12 of 19	1	NM_004070.4	ENSP00000332771.4

Frequencies

GnomAD3 genomes AF: 0.00669 AC: 1018 AN: 152130 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00172 AC: 431 AN: 250816 AF XY: 0.00130

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.000654

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000690 AC: 1008 AN: 1461450 Hom.: 7 Cov.: 34 AF XY: 0.000600 AC XY: 436 AN XY: 727032

African (AFR) AF: 0.0231 AC: 773 AN: 33476

American (AMR) AF: 0.000783 AC: 35 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53050

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000899 AC: 100 AN: 1111976

Other (OTH) AF: 0.00154 AC: 93 AN: 60388

GnomAD4 genome AF: 0.00669 AC: 1018 AN: 152248 Hom.: 20 Cov.: 33 AF XY: 0.00622 AC XY: 463 AN XY: 74440

African (AFR) AF: 0.0232 AC: 964 AN: 41548

American (AMR) AF: 0.00268 AC: 41 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67998

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.000306 Hom.: 0

Bravo AF: 0.00749

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 20, 2016

Athena Diagnostics

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
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs58210748; hg19: chr1-16355799;