1-11838976-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001286.5(CLCN6):c.2529+316G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 694,878 control chromosomes in the GnomAD database, including 24,531 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4411 hom., cov: 33)
  • Exomes 𝑓: 0.27 (20120 hom.)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.846

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015443265).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN6	NM_001286.5	c.2529+316G>T		intron_variant		ENST00000346436.11
CLCN6	NM_001256959.2	c.2463+316G>T		intron_variant
CLCN6	NR_046428.2	n.2585+316G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN6	ENST00000346436.11	c.2529+316G>T		intron_variant		1	NM_001286.5	P1
CLCN6	ENST00000376496.4	c.2845G>T	p.Asp949Tyr	missense_variant	22/22	5
CLCN6	ENST00000312413.10	c.2463+316G>T		intron_variant		2
CLCN6	ENST00000400892.3	c.*1022+316G>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35733 AN: 152006 Hom.: 4411 Cov.: 33

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.232

GnomAD3 exomes AF: 0.256 AC: 37382 AN: 146004 Hom.: 5167 AF XY: 0.266 AC XY: 20849 AN XY: 78344

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.225

Gnomad SAS exome AF: 0.371

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.266 AC: 144507 AN: 542754 Hom.: 20120 Cov.: 0 AF XY: 0.274 AC XY: 79075 AN XY: 288874

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.279

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.260

GnomAD4 genome AF: 0.235 AC: 35759 AN: 152124 Hom.: 4411 Cov.: 33 AF XY: 0.236 AC XY: 17545 AN XY: 74350

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.363

Gnomad4 FIN AF: 0.294

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.232

Alfa AF: 0.255 Hom.: 8548

Bravo AF: 0.221

TwinsUK AF: 0.274 AC: 1016

ALSPAC AF: 0.273 AC: 1052

ExAC AF: 0.210 AC: 6423

Asia WGS AF: 0.285 AC: 991 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	0.47
Dann	Benign	0.82
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	0.49	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Vest4		0.070
ClinPred		0.0035	T
GERP RS		-6.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1023252; hg19: chr1-11899033; COSMIC: COSV56738706; COSMIC: COSV56738706;