rs780580623
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2
The NM_006939.4(SOS2):c.674G>A(p.Arg225Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,600,092 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. R225L) has been classified as Uncertain significance.
Frequency
Consequence
NM_006939.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS2 | NM_006939.4 | c.674G>A | p.Arg225Gln | missense_variant | 5/23 | ENST00000216373.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.674G>A | p.Arg225Gln | missense_variant | 5/23 | 1 | NM_006939.4 | P1 | |
SOS2 | ENST00000543680.5 | c.674G>A | p.Arg225Gln | missense_variant | 5/22 | 1 | |||
SOS2 | ENST00000556469.5 | n.482-5931G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152130Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000296 AC: 7AN: 236676Hom.: 0 AF XY: 0.0000234 AC XY: 3AN XY: 128462
GnomAD4 exome AF: 0.000118 AC: 171AN: 1447962Hom.: 0 Cov.: 30 AF XY: 0.000105 AC XY: 76AN XY: 720472
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152130Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74324
ClinVar
Submissions by phenotype
Noonan syndrome 9 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 29, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2016 | The R225Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R225Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2021 | The p.R225Q variant (also known as c.674G>A), located in coding exon 5 of the SOS2 gene, results from a G to A substitution at nucleotide position 674. The arginine at codon 225 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | SOS2: BP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at