22-50523639-A-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PP3_Strong
The NM_005138.3(SCO2):āc.773T>Cā(p.Met258Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,690 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 (ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_005138.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCO2 | NM_005138.3 | c.773T>C | p.Met258Thr | missense_variant | 2/2 | ENST00000395693.8 | NP_005129.2 | |
NCAPH2 | NM_152299.4 | c.*264A>G | 3_prime_UTR_variant | 20/20 | ENST00000420993.7 | NP_689512.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCO2 | ENST00000395693.8 | c.773T>C | p.Met258Thr | missense_variant | 2/2 | 1 | NM_005138.3 | ENSP00000379046 | P1 | |
NCAPH2 | ENST00000420993.7 | c.*264A>G | 3_prime_UTR_variant | 20/20 | 1 | NM_152299.4 | ENSP00000410088 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 34
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461474Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727038
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1AN XY: 74362
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2023 | Variant summary: SCO2 c.773T>C (p.Met258Thr) results in a non-conservative amino acid change located in the Thioredoxin domain (IPR013766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251224 control chromosomes. c.773T>C has been reported in the literature as a compound heterozygous genotype in at least two individuals affected with SCO2-related conditions, specifically Leigh syndrome or Leigh-like syndrome (e.g., Ogawa_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31967322). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at