dbSNP rs1773492400: CLCN3:p.Gly33Asp (chr4-169636026-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001829.4(CLCN3):c.98G>A(p.Gly33Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G33V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CLCN3
NM_001829.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.26

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 link	c.98G>A	p.Gly33Asp	missense_variant	Exon 2 of 13	ENST00000513761.6	NP_001820.2	P51790-1
CLCN3	NM_173872.4 link	c.98G>A	p.Gly33Asp	missense_variant	Exon 2 of 14		NP_776297.2	P51790-2
CLCN3	NM_001243372.2 link	c.98G>A	p.Gly33Asp	missense_variant	Exon 2 of 12		NP_001230301.1	P51790-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN3	ENST00000513761.6 link	c.98G>A	p.Gly33Asp	missense_variant	Exon 2 of 13	1	NM_001829.4	ENSP00000424603.1		P51790-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;T;.;.;T

Eigen

Benign

0.075

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

D;D;D;D;D

M_CAP

Uncertain

0.092

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Uncertain

-0.090

MutationAssessor

Benign

1.8

.;L;L;L;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.5

N;N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.061

T;T;D;D;D

Sift4G

Benign

0.21

T;T;T;T;D

Polyphen

0.0070, 0.012

.;B;B;.;.

Vest4

0.71, 0.71, 0.70

MutPred

0.47

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.98

MPC

2.3

ClinPred

0.96

GERP RS

5.4

Varity_R

0.19

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over