rs138459515
Variant names:
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 (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
SOS2
NM_006939.4 missense
NM_006939.4 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 7.66
Genes affected
SOS2 (HGNC:11188): (SOS Ras/Rho guanine nucleotide exchange factor 2) This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAd4 at 14 AD gene.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.1868G>A | p.Arg623His | missense_variant | Exon 11 of 23 | 1 | NM_006939.4 | ENSP00000216373.5 | ||
SOS2 | ENST00000543680.5 | c.1769G>A | p.Arg590His | missense_variant | Exon 10 of 22 | 1 | ENSP00000445328.1 | |||
SOS2 | ENST00000555794.2 | c.980G>A | p.Arg327His | missense_variant | Exon 5 of 6 | 1 | ENSP00000484766.1 |
Frequencies
GnomAD3 genomes AF: 0.0000921 AC: 14AN: 152044Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000887 AC: 22AN: 247996Hom.: 0 AF XY: 0.0000894 AC XY: 12AN XY: 134174
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GnomAD4 exome AF: 0.000237 AC: 345AN: 1453618Hom.: 0 Cov.: 27 AF XY: 0.000231 AC XY: 167AN XY: 723558
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GnomAD4 genome AF: 0.0000921 AC: 14AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74256
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2025 | 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). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS2 protein function. 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. - |
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 - |
SOS2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 25, 2024 | The SOS2 c.1868G>A variant is predicted to result in the amino acid substitution p.Arg623His. This variant has been reported in an individual tested for bone marrow failure (Lauhasurayotin et al. 2019. PubMed ID: 31839986). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too high to be a primary cause of disease (Gelb et al. 2018. PubMed ID 29493581). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at