2-210647986-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_001875.5(CPS1):c.3265C>T(p.Arg1089Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1089L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001875.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CPS1 | NM_001875.5 | c.3265C>T | p.Arg1089Cys | missense_variant | 26/38 | ENST00000233072.10 | NP_001866.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461714Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727164
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Congenital hyperammonemia, type I Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 06, 2023 | 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 CPS1 protein function. ClinVar contains an entry for this variant (Variation ID: 551329). This missense change has been observed in individual(s) with CPS1-related conditions (PMID: 21120950, 33309754). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1089 of the CPS1 protein (p.Arg1089Cys). This variant disrupts the p.Arg1089 amino acid residue in CPS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15876373, 16737834). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 04, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in two individuals from a cohort of patients with CPS1 deficiency, however specific clinical information on patients was not provided, nor was the presence of a second variant in CPS1 discussed (Haberle et al., 2011); This variant is associated with the following publications: (PMID: 20800523, 21120950, 19092443, 19309799) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at