chr14-50118346-A-G
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_006939.4(SOS2):c.3997T>C(p.Ter1333ArgextTer2) variant causes a stop lost change. The variant allele was found at a frequency of 0.0000422 in 1,612,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000039 ( 0 hom. )
Consequence
SOS2
NM_006939.4 stop_lost
NM_006939.4 stop_lost
Scores
3
4
Clinical Significance
Conservation
PhyloP100: 7.11
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 -6 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_addAF=-0.0794762).
BS2
?
High AC in GnomAd at 11 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS2 | NM_006939.4 | c.3997T>C | p.Ter1333ArgextTer2 | stop_lost | 23/23 | ENST00000216373.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.3997T>C | p.Ter1333ArgextTer2 | stop_lost | 23/23 | 1 | NM_006939.4 | P1 | |
SOS2 | ENST00000543680.5 | c.3898T>C | p.Ter1300ArgextTer2 | stop_lost | 22/22 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000518 AC: 13AN: 250822Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135562
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GnomAD4 exome AF: 0.0000390 AC: 57AN: 1460826Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 726644
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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:3
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change results in a frameshift in the SOS2 gene (p.*1333Argext*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last amino acid of the SOS2 protein and extend the protein by 2 additional amino acid residues. This variant is present in population databases (rs142666803, gnomAD 0.04%). 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: 859843). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 | Genome-Nilou Lab | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 19, 2021 | Variant summary: SOS2 c.3997T>C (p.X1333ArgextX2) changes the termination codon and is predicted to lead to an extended protein with two additional amino acids added to the normal C-terminus. The variant allele was found at a frequency of 5.2e-05 in 250822 control chromosomes (gnomAD). The observed variant frequency is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. Activating mutations in SOS2 have been reported in patients with Noonan syndrome, however, the relevance of stop-codon read through variants on the associated mechanism and/or pathophysiology of Noonan syndrome is not clear. c.3997T>C has been reported in the literature in at-least one individual from a family reportedly affected with Brugada syndrome (Molina_2019). This report does not provide unequivocal conclusions about association of the variant with either Brugada syndrome or Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Noonan syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
N;N
Vest4
GERP RS
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