rs879255583
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001830.4(CLCN4):c.1664C>T(p.Ala555Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A555A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 24)
Consequence
CLCN4
NM_001830.4 missense
NM_001830.4 missense
Scores
9
3
3
Clinical Significance
Conservation
PhyloP100: 5.99
Genes affected
CLCN4 (HGNC:2022): (chloride voltage-gated channel 4) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. Chloride channel 4 has an evolutionary conserved CpG island and is conserved in both mouse and hamster. This gene is mapped in close proximity to APXL (Apical protein Xenopus laevis-like) and OA1 (Ocular albinism type I), which are both located on the human X chromosome at band p22.3. The physiological role of chloride channel 4 remains unknown but may contribute to the pathogenesis of neuronal disorders. Alternate splicing results in two transcript variants that encode different proteins. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001830.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, CLCN4
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
?
Variant X-10213768-C-T is Pathogenic according to our data. Variant chrX-10213768-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 209115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-10213768-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN4 | NM_001830.4 | c.1664C>T | p.Ala555Val | missense_variant | 11/13 | ENST00000380833.9 | |
CLCN4 | NM_001256944.2 | c.1382C>T | p.Ala461Val | missense_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN4 | ENST00000380833.9 | c.1664C>T | p.Ala555Val | missense_variant | 11/13 | 1 | NM_001830.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2022 | Published functional studies demonstrate A555V reduced the outwardly rectifying CIC-4 current, suggesting a damaging effect (Palmer et al,. 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633542, 34426522, 27550844) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 15, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 555 of the CLCN4 protein (p.Ala555Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CLCN4-related conditions (PMID: 27550844). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 209115). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN4 protein function. Experimental studies have shown that this missense change affects CLCN4 function (PMID: 27550844). For these reasons, this variant has been classified as Pathogenic. - |
CLCN4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Sydney Children's Hospital, SCHN | Mar 22, 2016 | De novo variant. Clinical phenotype consistent with case series of individuals with CLCN4 related disorder. - |
Intellectual disability, X-linked 49 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Gene2Care/ Palmer Lab, University of New South Wales | May 27, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, flagged submission | clinical testing | Ambry Genetics | Jun 06, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Benign
T;D;D
Sift4G
Benign
T;T;T
Polyphen
0.96
.;D;.
Vest4
MutPred
0.78
.;Gain of sheet (P = 0.0827);.;
MVP
MPC
2.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at