rs3737965

chr1-11806394-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001286.5(CLCN6):c.87+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0509 in 1,454,100 control chromosomes in the GnomAD database, including 2,228 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 0.043 (210 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2018 hom.)
• Consequence: CLCN6 NM_001286.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.49

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]

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN6	NM_001286.5	c.87+45G>A		intron_variant		ENST00000346436.11
CLCN6	NM_001256959.2	c.87+45G>A		intron_variant
CLCN6	NR_046428.2	n.159+45G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN6	ENST00000346436.11	c.87+45G>A		intron_variant		1	NM_001286.5	P1

Frequencies

GnomAD3 genomes AF: 0.0435 AC: 6615 AN: 152028 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0503 AC: 3575 AN: 71084 Hom.: 142 AF XY: 0.0540 AC XY: 2273 AN XY: 42114

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.0949

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0477

Gnomad OTH exome AF: 0.0387

GnomAD4 exome AF: 0.0517 AC: 67366 AN: 1301956 Hom.: 2018 Cov.: 26 AF XY: 0.0525 AC XY: 33690 AN XY: 642026

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.0410

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.0927

Gnomad4 FIN exome AF: 0.0180

Gnomad4 NFE exome AF: 0.0505

Gnomad4 OTH exome AF: 0.0582

GnomAD4 genome AF: 0.0435 AC: 6612 AN: 152144 Hom.: 210 Cov.: 32 AF XY: 0.0431 AC XY: 3206 AN XY: 74400

Gnomad4 AFR AF: 0.0307

Gnomad4 AMR AF: 0.0432

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0467

Gnomad4 OTH AF: 0.0450

Alfa AF: 0.0433 Hom.: 70

Bravo AF: 0.0433

Asia WGS AF: 0.111 AC: 383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs3737965; hg19: chr1-11866451; COSMIC: COSV56743387; COSMIC: COSV56743387;