4-169636017-A-G

Variant names:

• chr4-169636017-A-G
• NM_001829.4:c.89A>G

Variant summary

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

The NM_001829.4(CLCN3):​c.89A>G​(p.Asp30Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCN3 NM_001829.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.63

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.89A>G	p.Asp30Gly	missense_variant	Exon 2 of 13	ENST00000513761.6	NP_001820.2
CLCN3	NM_173872.4	c.89A>G	p.Asp30Gly	missense_variant	Exon 2 of 14		NP_776297.2
CLCN3	NM_001243372.2	c.89A>G	p.Asp30Gly	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.89A>G	p.Asp30Gly	missense_variant	Exon 2 of 13	1	NM_001829.4	ENSP00000424603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89A>G (p.D30G) alteration is located in exon 1 (coding exon 1) of the CLCN3 gene. This alteration results from a A to G substitution at nucleotide position 89, causing the aspartic acid (D) at amino acid position 30 to be replaced by a glycine (G). 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	0.33
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;T;.;.;T
Eigen	Benign	0.051
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Uncertain	0.0079	D
MutationAssessor	Benign	1.8	.;L;L;L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.092	T;T;D;T;T
Sift4G	Uncertain	0.013	D;T;T;T;D
Polyphen		0.016, 0.012	.;B;B;.;.
Vest4		0.69, 0.70, 0.68
MutPred		0.35		Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP		0.97
MPC		2.3
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.23
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-170557168; COSMIC: COSV61628020;