14-50158631-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_006939.4(SOS2):c.1868G>A(p.Arg623His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,605,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R623C) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS2 | NM_006939.4 | c.1868G>A | p.Arg623His | missense_variant | 11/23 | ENST00000216373.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.1868G>A | p.Arg623His | missense_variant | 11/23 | 1 | NM_006939.4 | P1 | |
SOS2 | ENST00000543680.5 | c.1769G>A | p.Arg590His | missense_variant | 10/22 | 1 | |||
SOS2 | ENST00000555794.2 | c.983G>A | p.Arg328His | missense_variant | 5/6 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000921 AC: 14AN: 152044Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000887 AC: 22AN: 247996Hom.: 0 AF XY: 0.0000894 AC XY: 12AN XY: 134174
GnomAD4 exome AF: 0.000237 AC: 345AN: 1453618Hom.: 0 Cov.: 27 AF XY: 0.000231 AC XY: 167AN XY: 723558
GnomAD4 genome AF: 0.0000921 AC: 14AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74256
ClinVar
Submissions by phenotype
Noonan syndrome 9 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 05, 2022 | The SOS2 c.1868G>A (p.Arg623His) missense change has a maximum subpopulation frequency of 0.017% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Noonan syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Jun 11, 2021 | The p.Arg623His variant in the SOS2 gene has been previously reported in 1 individual with myelodysplastic syndrome (Lauhasurayotin et al., 2019). This variant has been identified in 22/128,178 European (non-Finnish) chromosomes (24/279,372 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a high enough frequency to rule out pathogenicity. Computational tools do not predict that the p.Arg623His variant impacts protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg623His variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: None - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 623 of the SOS2 protein (p.Arg623His). This variant is present in population databases (rs138459515, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SOS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 542401). 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 SOS2 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