rs557671802
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001352252.2(CARS2):c.-35C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000938 in 1,599,736 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 Uncertain significance (★).
Frequency
Consequence
NM_001352252.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000245 AC: 6AN: 244818Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132666
GnomAD4 exome AF: 0.00000898 AC: 13AN: 1447468Hom.: 0 Cov.: 31 AF XY: 0.00000697 AC XY: 5AN XY: 717698
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74456
ClinVar
Submissions by phenotype
Combined oxidative phosphorylation defect type 27 Pathogenic:1Uncertain:1
- -
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 251 of the CARS2 protein (p.Pro251Leu). This variant is present in population databases (rs557671802, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of a CARS2-related condition (PMID: 25787132). ClinVar contains an entry for this variant (Variation ID: 218178). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CARS2 protein function with a positive predictive value of 80%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at