chr4-169635978-A-G

Position:

• chr4-169635978-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001829.4(CLCN3):​c.50A>G​(p.Asn17Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,460,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• 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]

CLCN3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• 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=0.24651459).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN3	NM_001829.4	c.50A>G	p.Asn17Ser	missense_variant	2/13	ENST00000513761.6	NP_001820.2
CLCN3	NM_173872.4	c.50A>G	p.Asn17Ser	missense_variant	2/14		NP_776297.2
CLCN3	NM_001243372.2	c.50A>G	p.Asn17Ser	missense_variant	2/12		NP_001230301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN3	ENST00000513761.6	c.50A>G	p.Asn17Ser	missense_variant	2/13	1	NM_001829.4	ENSP00000424603.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250644 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135510

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460944 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 726794

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: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000514 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000547

EpiControl AF: 0.000119

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

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Nov 24, 2023

This sequence variant is a single nucleotide substitution (A>G) at position 50 of the coding sequence of the CLCN3 gene that results in an asparagine to serine amino acid change at residue 17 of the chloride voltage-gated channel 3 protein. This variant is absent from ClinVar and has not been observed in individuals affected by a CLCN3-related disorder in the published literature, to our knowledge. This variant is present in 8 of 250644 alleles (0.0032%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this Asn to Ser amino acid change would be neutral, and the Asn17 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP4, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	.;T;.;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.068
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.1	.;L;L;L;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.74	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;D
Polyphen		0.011, 0.019	.;B;B;.;.
Vest4		0.56, 0.56, 0.55
MVP		0.75
MPC		1.8
ClinPred		0.25	T
GERP RS		5.4
Varity_R		0.071
gMVP		0.53

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: rs757213816; hg19: chr4-170557129;