2-39058774-T-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_005633.4(SOS1):c.244A>G(p.Ile82Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000354 in 1,612,340 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152026Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250518Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135462
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1460314Hom.: 0 Cov.: 29 AF XY: 0.0000289 AC XY: 21AN XY: 726446
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152026Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74234
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The p.Ile82Val vari ant in SOS1 has been identified by our laboratory in 1 child with Shone's comple x and 1 infant with clinical features of Noonan syndrome; however, both of these individuals inherited this variant from reportedly unaffected parents. This var iant has also been identified in 2/66566 European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517157). Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, while the clinical sign ificance of the p.Ile82val variant is uncertain, the identification of this vari ant in an individual with unrelated features and inheritance from unaffected par ents suggest that it is more likely to be benign. -
Noonan syndrome Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.I82V variant (also known as c.244A>G), located in coding exon 3 of the SOS1 gene, results from an A to G substitution at nucleotide position 244. The isoleucine at codon 82 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in a cohort of children with multiple cafe-au-lait macules; however, clinical details were limited (Castellanos E et al. Clin Genet, 2020 02;97:264-275). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -
RASopathy Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 82 of the SOS1 protein (p.Ile82Val). This variant is present in population databases (rs397517157, gnomAD 0.02%). This missense change has been observed in individual(s) with Shone's complex or clinical features of Noonan syndrome (ClinVar Variation ID: 45351). ClinVar contains an entry for this variant (Variation ID: 45351). 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 SOS1 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. -
not provided Benign:1
See Variant Classification Assertion Criteria. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at