rs587777161
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001830.4(CLCN4):c.1630G>A(p.Gly544Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G544E) has been classified as Pathogenic.
Frequency
Consequence
NM_001830.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 23 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN4 | NM_001830.4 | c.1630G>A | p.Gly544Arg | missense_variant | 11/13 | ENST00000380833.9 | |
CLCN4 | NM_001256944.2 | c.1348G>A | p.Gly450Arg | missense_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN4 | ENST00000380833.9 | c.1630G>A | p.Gly544Arg | missense_variant | 11/13 | 1 | NM_001830.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Intellectual disability, X-linked 49 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 04, 2022 | This variant was identified as hemizygous._x000D_ Criteria applied: PS1, PS2, PM1, PS4_SUP, PM2_SUP, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000100781 / PMID: 23647072). The variant has been previously reported as de novo in a similarly affected individual (PMID: 23647072). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2013 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2021 | Published functional studies demonstrate an almost abolishment of ClC-4 currents that lead to a damaging effect (Veeramah et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23647072, 27550844) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at