4-169635960-A-G

Variant names:

• chr4-169635960-A-G
• rs1553965256
• NM_001829.4:c.32A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001829.4(CLCN3):​c.32A>G​(p.Tyr11Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLCN3 NM_001829.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CLCN3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 4.3745 (above the threshold of 3.09). Trascript score misZ: 5.1954 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with seizures and brain abnormalities, complex neurodevelopmental disorder, neurodevelopmental disorder with hypotonia and brain abnormalities.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN3	NM_001829.4	c.32A>G	p.Tyr11Cys	missense_variant	Exon 2 of 13	ENST00000513761.6	NP_001820.2
CLCN3	NM_173872.4	c.32A>G	p.Tyr11Cys	missense_variant	Exon 2 of 14		NP_776297.2
CLCN3	NM_001243372.2	c.32A>G	p.Tyr11Cys	missense_variant	Exon 2 of 12		NP_001230301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN3	ENST00000513761.6	c.32A>G	p.Tyr11Cys	missense_variant	Exon 2 of 13	1	NM_001829.4	ENSP00000424603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459234 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000550

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32A>G (p.Y11C) alteration is located in exon 2 (coding exon 1) of the CLCN3 gene. This alteration results from an A to G substitution at nucleotide position 32, causing the tyrosine (Y) at amino acid position 11 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. The tyrosine (Tyr) at amino acid position 11 is located in the cytoplasmic N-terminal region of the long isoforms of ClC-3 – ClC-a, ClC-b and ClC-e encoded by alternatively spliced transcripts NM_001243372, NM_001829 and NM_173872, and is absent in the short isoform ClC-3c encoded by transcript NM_001243374 that has an alternate start codon further downstream. Homologous transcripts of ClC-3b, ClC-c and ClC-e have been described in the mouse out of which ClC-b and ClC-c are found to be ubiquitously expressed with a high expression in the brain, while ClC-e is expressed only in the retina, pancreas, kidney, liver and lung (Guzman, 2015). Dileucine motifs near the Tyr11 residue in the N-terminal of the ClC-3 protein have been shown to be involved in clathrin-mediated endocytosis of the protein from the plasma membrane (Zhao, 2007). Mutations of these motifs abolish the endocytosis of ClC-3 and increase its surface expression thereby preventing it from internalization to its appropriate subcellular location. However, functional studies of the Tyr11 residue have not been performed to determine its role in the trafficking or function of ClC-3. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.4	.;L;L;L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;.
Vest4		0.53, 0.61, 0.52
MutPred		0.45		Gain of glycosylation at S15 (P = 0.0258);Gain of glycosylation at S15 (P = 0.0258);Gain of glycosylation at S15 (P = 0.0258);Gain of glycosylation at S15 (P = 0.0258);Gain of glycosylation at S15 (P = 0.0258);
MVP		0.95
MPC		2.3
ClinPred		0.92	D
GERP RS		2.9
Varity_R		0.14
gMVP		0.52

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: rs1553965256; hg19: chr4-170557111;