4-169689225-G-A

Position:

• chr4-169689225-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001829.4(CLCN3):​c.601G>A​(p.Ala201Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 6.76

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CLCN3. . Gene score misZ 4.3745 (greater than the threshold 3.09). Trascript score misZ 5.1954 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with seizures and brain abnormalities, complex neurodevelopmental disorder, neurodevelopmental disorder with hypotonia and brain abnormalities.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33186048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN3	NM_001829.4	c.601G>A	p.Ala201Thr	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.601G>A	p.Ala201Thr	missense_variant	5/13	1	NM_001829.4	ENSP00000424603.1
CLCN3	ENST00000347613.9	c.601G>A	p.Ala201Thr	missense_variant	5/14	1		ENSP00000261514.5
CLCN3	ENST00000360642.7	c.601G>A	p.Ala201Thr	missense_variant	5/12	2		ENSP00000353857.3
CLCN3	ENST00000507875.6	c.520G>A	p.Ala174Thr	missense_variant	4/12	2		ENSP00000425323.2

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2021

The c.601G>A (p.A201T) alteration is located in exon 1 (coding exon 1) of the CLCN3 gene. This alteration results from a G to A substitution at nucleotide position 601, causing the alanine (A) at amino acid position 201 to be replaced by a threonine (T). 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	0.084
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;.;.;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D;D;T;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	-0.69	N;N;N;.;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.19	N;N;N;N;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.56	T;T;T;T;.;T
Sift4G	Benign	0.41	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.
Vest4		0.37
MutPred		0.39		Loss of glycosylation at S206 (P = 0.0254);Loss of glycosylation at S206 (P = 0.0254);Loss of glycosylation at S206 (P = 0.0254);.;.;.;
MVP		0.77
MPC		1.2
ClinPred		0.88	D
GERP RS		5.4
Varity_R		0.17
gMVP		0.80

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: chr4-170610376;