chr14-50118391-G-A
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_006939.4(SOS2):c.3952C>T(p.Pro1318Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,614,102 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1318A) has been classified as Benign.
Frequency
Consequence
NM_006939.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS2 | NM_006939.4 | c.3952C>T | p.Pro1318Ser | missense_variant | 23/23 | ENST00000216373.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.3952C>T | p.Pro1318Ser | missense_variant | 23/23 | 1 | NM_006939.4 | P1 | |
SOS2 | ENST00000543680.5 | c.3853C>T | p.Pro1285Ser | missense_variant | 22/22 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000506 AC: 77AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000497 AC: 125AN: 251440Hom.: 0 AF XY: 0.000552 AC XY: 75AN XY: 135886
GnomAD4 exome AF: 0.000792 AC: 1158AN: 1461860Hom.: 1 Cov.: 32 AF XY: 0.000796 AC XY: 579AN XY: 727234
GnomAD4 genome ? AF: 0.000506 AC: 77AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36AN XY: 74438
ClinVar
Submissions by phenotype
Noonan syndrome 9 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | SOS2: BP4, BS1, BS2 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 15, 2023 | Variant summary: SOS2 c.3952C>T (p.Pro1318Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 251440 control chromosomes, predominantly at a frequency of 0.00095 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 380 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3952C>T has been reported in the literature in an individual affected with Noonan Syndrome and Related Conditions, without strong evidence for causality (Cordeddu_2015). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26173643). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
SOS2-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 30, 2020 | 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). - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at