rs779824005
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP2PP3BS2
The NM_001830.4(CLCN4):c.2153G>A(p.Arg718Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,210,197 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R718W) has been classified as Pathogenic.
Frequency
Consequence
NM_001830.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN4 | NM_001830.4 | c.2153G>A | p.Arg718Gln | missense_variant | 12/13 | ENST00000380833.9 | |
CLCN4 | NM_001256944.2 | c.1871G>A | p.Arg624Gln | missense_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN4 | ENST00000380833.9 | c.2153G>A | p.Arg718Gln | missense_variant | 12/13 | 1 | NM_001830.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000268 AC: 3AN: 112147Hom.: 0 Cov.: 22 AF XY: 0.0000583 AC XY: 2AN XY: 34305
GnomAD3 exomes AF: 0.0000109 AC: 2AN: 183435Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67869
GnomAD4 exome AF: 0.00000729 AC: 8AN: 1098050Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 363404
GnomAD4 genome ? AF: 0.0000268 AC: 3AN: 112147Hom.: 0 Cov.: 22 AF XY: 0.0000583 AC XY: 2AN XY: 34305
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 718 of the CLCN4 protein (p.Arg718Gln). This variant is present in population databases (rs779824005, gnomAD 0.004%). This missense change has been observed in individual(s) with CLCN4-related conditions (PMID: 36385166). ClinVar contains an entry for this variant (Variation ID: 521940). 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 does not substantially affect CLCN4 function (PMID: 36385166). This variant disrupts the p.Arg718 amino acid residue in CLCN4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27550844, 29314583). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 19, 2022 | Identified as a paternally inherited variant in an individual from a cohort of patients with autism spectrum disorder in published literature (Geisheker et al., 2017); 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: 26034137, 28628100, 27550844, 25644381, 23647072) - |
Intellectual disability, X-linked 49 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 23, 2021 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 14, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
See cases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli | Dec 07, 2022 | PM1_moderate;PM2_supporting;PM5_moderate;PP2_supporting;PP3_supporting;BS3_strong;B4_strong. In a subsequent segregation study, the variant was also observed in an unaffected male family member. For this reason, the variant was reclassified from likely pathogenic to likely benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at