1-16032437-T-C

Position:

• chr1-16032437-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004070.4(CLCNKA):​c.1846-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,608,830 control chromosomes in the GnomAD database, including 372,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37830 hom., cov: 33)
  • Exomes 𝑓: 0.67 (334827 hom.)
• Consequence: CLCNKA NM_004070.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005001
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0590

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-16032437-T-C is Benign according to our data. Variant chr1-16032437-T-C is described in ClinVar as [Benign]. Clinvar id is 585696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCNKA	NM_004070.4	c.1846-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000331433.5
CLCNKA	NM_001042704.2	c.1846-9T>C		splice_polypyrimidine_tract_variant, intron_variant
CLCNKA	NM_001257139.2	c.1717-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCNKA	ENST00000331433.5	c.1846-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004070.4	P4
CLCNKA	ENST00000375692.5	c.1846-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1		A1
CLCNKA	ENST00000439316.6	c.1717-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2
CLCNKA	ENST00000464764.5	n.2450-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106598 AN: 152028 Hom.: 37803 Cov.: 33

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.975

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.705

GnomAD3 exomes AF: 0.682 AC: 171024 AN: 250740 Hom.: 59411 AF XY: 0.678 AC XY: 91983 AN XY: 135700

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.597

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.971

Gnomad SAS exome AF: 0.620

Gnomad FIN exome AF: 0.712

Gnomad NFE exome AF: 0.670

Gnomad OTH exome AF: 0.667

GnomAD4 exome AF: 0.675 AC: 983127 AN: 1456684 Hom.: 334827 Cov.: 35 AF XY: 0.673 AC XY: 487813 AN XY: 724878

Gnomad4 AFR exome AF: 0.773

Gnomad4 AMR exome AF: 0.603

Gnomad4 ASJ exome AF: 0.585

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.615

Gnomad4 FIN exome AF: 0.716

Gnomad4 NFE exome AF: 0.668

Gnomad4 OTH exome AF: 0.684

GnomAD4 genome AF: 0.701 AC: 106675 AN: 152146 Hom.: 37830 Cov.: 33 AF XY: 0.699 AC XY: 52020 AN XY: 74384

Gnomad4 AFR AF: 0.762

Gnomad4 AMR AF: 0.634

Gnomad4 ASJ AF: 0.589

Gnomad4 EAS AF: 0.975

Gnomad4 SAS AF: 0.636

Gnomad4 FIN AF: 0.706

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.705

Alfa AF: 0.659 Hom.: 12469

Bravo AF: 0.698

Asia WGS AF: 0.791 AC: 2750 AN: 3478

EpiCase AF: 0.655

EpiControl AF: 0.662

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -

Bartter disease type 4B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.9
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.020
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

Publications

LitVar

Other links and lift over

dbSNP: rs10803407; hg19: chr1-16358932;