rs17376328

chr1-11816605-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001286.5(CLCN6):c.214-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,610,052 control chromosomes in the GnomAD database, including 2,260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.044 (191 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2069 hom.)
• Consequence: CLCN6 NM_001286.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004344
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.69

Genes affected

CLCN6 (HGNC:2024): (chloride voltage-gated channel 6) This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-11816605-G-A is Benign according to our data. Variant chr1-11816605-G-A is described in ClinVar as [Benign]. Clinvar id is 1601467.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN6	NM_001286.5	c.214-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000346436.11
CLCN6	NM_001256959.2	c.148-10G>A		splice_polypyrimidine_tract_variant, intron_variant
CLCN6	NR_046428.2	n.286-10G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN6	ENST00000346436.11	c.214-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001286.5	P1

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6648 AN: 152154 Hom.: 191 Cov.: 33

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0434 AC: 10744 AN: 247304 Hom.: 328 AF XY: 0.0446 AC XY: 5963 AN XY: 133734

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0441

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.0536

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0505 AC: 73614 AN: 1457780 Hom.: 2069 Cov.: 30 AF XY: 0.0504 AC XY: 36535 AN XY: 725064

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.0176

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0449

Gnomad4 FIN exome AF: 0.0932

Gnomad4 NFE exome AF: 0.0542

Gnomad4 OTH exome AF: 0.0435

GnomAD4 genome AF: 0.0437 AC: 6647 AN: 152272 Hom.: 191 Cov.: 33 AF XY: 0.0456 AC XY: 3396 AN XY: 74450

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.0197

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0427

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.0549

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0474 Hom.: 287

Bravo AF: 0.0358

Asia WGS AF: 0.0150 AC: 54 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	5.1
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.13
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

Publications

LitVar

Other links and lift over

dbSNP: rs17376328; hg19: chr1-11876662; COSMIC: COSV56743999;