chr4-169635960-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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, Ambry Genetics, Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with seizures and brain abnormalities

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 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, neurodevelopmental disorder with hypotonia and brain abnormalities, complex neurodevelopmental disorder.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN3	NM_001829.4	MANE Select	c.32A>G	p.Tyr11Cys	missense	Exon 2 of 13	NP_001820.2
	CLCN3	NM_173872.4		c.32A>G	p.Tyr11Cys	missense	Exon 2 of 14	NP_776297.2
	CLCN3	NM_001243372.2		c.32A>G	p.Tyr11Cys	missense	Exon 2 of 12	NP_001230301.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN3	ENST00000513761.6	TSL:1 MANE Select	c.32A>G	p.Tyr11Cys	missense	Exon 2 of 13	ENSP00000424603.1
	CLCN3	ENST00000347613.9	TSL:1	c.32A>G	p.Tyr11Cys	missense	Exon 2 of 14	ENSP00000261514.5
	CLCN3	ENST00000360642.7	TSL:2	c.32A>G	p.Tyr11Cys	missense	Exon 2 of 12	ENSP00000353857.3

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

African (AFR) AF: 0.00 AC: 0 AN: 33318

American (AMR) AF: 0.00 AC: 0 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 85944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110648

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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 v4.9

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
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.45		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
Mutation Taster		=62/38	polymorphism

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: rs1553965256; hg19: chr4-170557111;