rs28937598
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_005138.3(SCO2):c.511C>T(p.Arg171Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,642 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R171Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_005138.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCO2 | NM_005138.3 | c.511C>T | p.Arg171Trp | missense_variant | 2/2 | ENST00000395693.8 | |
NCAPH2 | NM_152299.4 | c.*526G>A | 3_prime_UTR_variant | 20/20 | ENST00000420993.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCO2 | ENST00000395693.8 | c.511C>T | p.Arg171Trp | missense_variant | 2/2 | 1 | NM_005138.3 | P1 | |
NCAPH2 | ENST00000420993.7 | c.*526G>A | 3_prime_UTR_variant | 20/20 | 1 | NM_152299.4 | P4 | ||
ENST00000608319.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251114Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135784
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461454Hom.: 0 Cov.: 74 AF XY: 0.00000688 AC XY: 5AN XY: 727050
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 22, 2000 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 171 of the SCO2 protein (p.Arg171Trp). This variant is present in population databases (rs28937598, gnomAD 0.006%). This missense change has been observed in individual(s) with cardioencephalomyopathy due to mitochondrial complex IV deficiency (PMID: 10749987). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5680). 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 SCO2 protein function. Experimental studies have shown that this missense change affects SCO2 function (PMID: 18804471, 23345593, 25959673, 30593977). 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