rs773672997

Positions:

• chr14-50145585-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_006939.4(SOS2):​c.2396C>T​(p.Pro799Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,439,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.93

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.2396C>T	p.Pro799Leu	missense_variant	15/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.2396C>T	p.Pro799Leu	missense_variant	15/23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.2297C>T	p.Pro766Leu	missense_variant	14/22	1		ENSP00000445328.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000173 AC: 4 AN: 230768 Hom.: 0 AF XY: 0.0000240 AC XY: 3 AN XY: 125070

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000383

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000932

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000625 AC: 9 AN: 1439814 Hom.: 0 Cov.: 29 AF XY: 0.00000977 AC XY: 7 AN XY: 716290

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2023	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS2 protein function. ClinVar contains an entry for this variant (Variation ID: 567315). This variant has not been reported in the literature in individuals affected with SOS2-related conditions. This variant is present in population databases (rs773672997, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 799 of the SOS2 protein (p.Pro799Leu). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

Noonan syndrome 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

-

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2024

The p.P799L variant (also known as c.2396C>T), located in coding exon 15 of the SOS2 gene, results from a C to T substitution at nucleotide position 2396. The proline at codon 799 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-9.1	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.70		Gain of stability (P = 0.025);.;
MVP		0.71
MPC		0.67
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs773672997; hg19: chr14-50612303;