rs10520159

Variant names:

• chr4-169660075-G-A
• rs10520159
• NM_001829.4:c.161-19975G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

CLCN3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Illumina
• neurodevelopmental disorder with hypotonia and brain abnormalities

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics, Ambry Genetics
• neurodevelopmental disorder with seizures and brain abnormalities

  Inheritance: AR Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000303860 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001829.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN3	NM_001829.4	MANE Select	c.161-19975G>A		intron	N/A	NP_001820.2	P51790-1
	CLCN3	NM_173872.4		c.161-19975G>A		intron	N/A	NP_776297.2	P51790-2
	CLCN3	NM_001243372.2		c.161-19975G>A		intron	N/A	NP_001230301.1	P51790-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN3	ENST00000513761.6	TSL:1 MANE Select	c.161-19975G>A		intron	N/A	ENSP00000424603.1	P51790-1
	CLCN3	ENST00000347613.9	TSL:1	c.161-19975G>A		intron	N/A	ENSP00000261514.5	P51790-2
	CLCN3	ENST00000898875.1		c.161-5682G>A		intron	N/A	ENSP00000568934.1

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

African (AFR) AF: 0.128 AC: 2244 AN: 17532

American (AMR) AF: 0.0591 AC: 131 AN: 2218

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 721 AN: 7090

East Asian (EAS) AF: 0.0251 AC: 175 AN: 6980

South Asian (SAS) AF: 0.104 AC: 1768 AN: 16936

European-Finnish (FIN) AF: 0.0875 AC: 201 AN: 2296

Middle Eastern (MID) AF: 0.0548 AC: 101 AN: 1842

European-Non Finnish (NFE) AF: 0.0804 AC: 63441 AN: 789142

Other (OTH) AF: 0.0813 AC: 2467 AN: 30328

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

African (AFR) AF: 0.121 AC: 5030 AN: 41498

American (AMR) AF: 0.0540 AC: 826 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3468

East Asian (EAS) AF: 0.0293 AC: 152 AN: 5184

South Asian (SAS) AF: 0.101 AC: 485 AN: 4806

European-Finnish (FIN) AF: 0.109 AC: 1153 AN: 10586

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0823 AC: 5594 AN: 68004

Other (OTH) AF: 0.0770 AC: 163 AN: 2116

Alfa AF: 0.0898 Hom.: 367

Bravo AF: 0.0876

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		0.0020
PromoterAI		-0.084	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10520159; hg19: chr4-170581226;