4-169689090-C-G

Position:

• chr4-169689090-C-G

Variant summary

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

The NM_001829.4(CLCN3):​c.466C>G​(p.Leu156Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCN3 NM_001829.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.986

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/exons	MANE	Protein	UniProt
CLCN3	NM_001829.4	c.466C>G	p.Leu156Val	missense_variant	5/13	ENST00000513761.6	NP_001820.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN3	ENST00000513761.6	c.466C>G	p.Leu156Val	missense_variant	5/13	1	NM_001829.4	ENSP00000424603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with hypotonia and brain abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion, Medical Genetics

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. The variant is in trans with the NM_001829.4:c.491C>T variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.54). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	.;D;.;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.8	.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;D;D;D;D;.;D
REVEL	Pathogenic	0.65
Sift	Benign	0.042	D;D;D;D;D;.;D
Sift4G	Uncertain	0.013	D;D;D;D;T;T;T
Polyphen		0.10, 0.40, 0.24	.;B;B;.;B;.;.
Vest4		0.69, 0.68, 0.66, 0.69, 0.69
MutPred		0.45		Gain of methylation at K157 (P = 0.0413);Gain of methylation at K157 (P = 0.0413);Gain of methylation at K157 (P = 0.0413);Gain of methylation at K157 (P = 0.0413);.;.;.;
MVP		0.99
MPC		1.2
ClinPred		0.57	D
GERP RS		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.93

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: rs1581252557; hg19: chr4-170610241;