chr16-1461460-T-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001287.6(CLCN7):c.296A>G(p.Tyr99Cys) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y99H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001287.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN7 | NM_001287.6 | c.296A>G | p.Tyr99Cys | missense_variant | 4/25 | ENST00000382745.9 | |
CLCN7 | NM_001114331.3 | c.224A>G | p.Tyr75Cys | missense_variant | 3/24 | ||
CLCN7 | XM_011522354.2 | c.122A>G | p.Tyr41Cys | missense_variant | 4/25 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN7 | ENST00000382745.9 | c.296A>G | p.Tyr99Cys | missense_variant | 4/25 | 1 | NM_001287.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 29, 2023 | For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt CLCN7 protein function. ClinVar contains an entry for this variant (Variation ID: 56890). This missense change has been observed in individuals with autosomal dominant osteopetrosis (PMID: 23296056, 26056022, 30229577). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 99 of the CLCN7 protein (p.Tyr99Cys). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2017 | The Y99C variant in the CLCN7 gene has been reported previously in the heterozygous state in several unrelated individuals with osteopetrosis, including two families with segregation in multiple affected individuals (Del Fattore et al., 2006; Zheng et al., 2016; Sui et al., 2013). In addition, Y99C was reported in the homozygous state in a male child with infantile malignant osteopetrosis (Barvencik et al., 2014). The Y99C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y99C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The Y99C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Autosomal dominant osteopetrosis 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Guangxi Key laboratory of Metabolic Diseases Research; Guilin 181st Hospital | - | - - |
Autosomal recessive osteopetrosis 4 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at