rs10520159

Positions:

• chr4-169660075-G-A

Variant summary

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

The NM_001829.4(CLCN3):​c.161-19975G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0829 in 1,026,518 control chromosomes in the GnomAD database, including 3,684 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 0.091 (658 hom., cov: 32)
  • Exomes 𝑓: 0.081 (3026 hom.)
• Consequence: CLCN3 NM_001829.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200

Genes affected

CLCN3 (HGNC:2021): (chloride voltage-gated channel 3) This gene encodes a member of the voltage-gated chloride channel (ClC) family. The encoded protein is present in all cell types and localized in plasma membranes and in intracellular vesicles. It is a multi-pass membrane protein which contains a ClC domain and two additional C-terminal CBS (cystathionine beta-synthase) domains. The ClC domain catalyzes the selective flow of Cl- ions across cell membranes, and the CBS domain may have a regulatory function. This protein plays a role in both acidification and transmitter loading of GABAergic synaptic vesicles, and in smooth muscle cell activation and neointima formation. This protein is required for lysophosphatidic acid (LPA)-activated Cl- current activity and fibroblast-to-myofibroblast differentiation. The protein activity is regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in glioma cells. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN3	NM_001829.4	c.161-19975G>A		intron_variant		ENST00000513761.6	NP_001820.2
CLCN3	NM_173872.4	c.161-19975G>A		intron_variant			NP_776297.2
CLCN3	NM_001243372.2	c.161-19975G>A		intron_variant			NP_001230301.1
CLCN3	XM_047449584.1	c.-14-19975G>A		intron_variant			XP_047305540.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN3	ENST00000513761.6	c.161-19975G>A		intron_variant		1	NM_001829.4	ENSP00000424603.1

Frequencies

GnomAD3 genomes AF: 0.0909 AC: 13822 AN: 152036 Hom.: 656 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.0541

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0823

Gnomad OTH AF: 0.0774

GnomAD4 exome AF: 0.0815 AC: 71249 AN: 874364 Hom.: 3026 Cov.: 31 AF XY: 0.0808 AC XY: 32778 AN XY: 405482

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0591

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.0251

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.0875

Gnomad4 NFE exome AF: 0.0804

Gnomad4 OTH exome AF: 0.0813

GnomAD4 genome AF: 0.0909 AC: 13836 AN: 152154 Hom.: 658 Cov.: 32 AF XY: 0.0916 AC XY: 6814 AN XY: 74378

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0540

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.0293

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0823

Gnomad4 OTH AF: 0.0770

Alfa AF: 0.0904 Hom.: 340

Bravo AF: 0.0876

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.87

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: rs10520159; hg19: chr4-170581226;