rs201701595
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_006939.4(SOS2):c.858+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,180 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.00098 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 5 hom. )
Consequence
SOS2
NM_006939.4 intron
NM_006939.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.598
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 Benign. Variant got -16 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
Variant 14-50182454-T-C is Benign according to our data. Variant chr14-50182454-T-C is described in ClinVar as [Benign]. Clinvar id is 475763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 149 AD gene.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.858+9A>G | intron_variant | 1 | NM_006939.4 | ENSP00000216373.5 | ||||
SOS2 | ENST00000543680.5 | c.858+9A>G | intron_variant | 1 | ENSP00000445328.1 | |||||
SOS2 | ENST00000556469.5 | n.*1A>G | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000979 AC: 149AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00114 AC: 286AN: 250938Hom.: 4 AF XY: 0.00116 AC XY: 158AN XY: 135640
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GnomAD4 exome AF: 0.00144 AC: 2109AN: 1460824Hom.: 5 Cov.: 30 AF XY: 0.00143 AC XY: 1037AN XY: 726744
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GnomAD4 genome AF: 0.000978 AC: 149AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66AN XY: 74512
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ClinVar
Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Noonan syndrome 9 Benign:3
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 13, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2017 | Variant summary: The SOS2 c.858+9A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing while ESE finder predicts loss of the SRp40 binding motif. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been found in a large, broad control population, ExAC in 131/120310 control chromosomes (3 homozygotes) at a frequency of 0.0010889, which is approximately 436 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | SOS2: BS1, BS2 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
SOS2-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 23, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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BayesDel_noAF
Benign
CADD
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DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at