SOS2

protein-coding

SOS Ras/Rho guanine nucleotide exchange factor 2, the group of Dbl family Rho GEFs|Pleckstrin homology domain containing

Gene summary

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]

MANE transcript

NM_006939.4

Inheritance

ClinVar variants

P:15U:952B:645

Top phenotype

Noonan syndrome 9

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr14:50,117,130-50,231,578

External References & Databases

Ensembl (ENSG00000100485)

Transcript & Mutation Effects

hg38 • Region Span ~114.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Noonan syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: ClinGen

SOS2 was first reported in relation to autosomal dominant Noonan syndrome (NS) as early as 2015 (Yamamoto et al.; PMID: 25795793). At least 8 variants (7 missense, 1 in-frame indel) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes 8 variants in 12 probands reported in 4 publications (PMIDs: 25795793, 26173643, 30707178, 32788663). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is gain of function (PMID: 26173643). This gene-disease association is also supported by experimental evidence demonstrating that SOS2 is involved in the Ras/MAPK pathway, which is associated with the NS phenotype (PMIDs: 26446362, 26173643, 10938118, 23875798). Of note, the ClinGen RASopathy Expert Panel found no published evidence associating SOS2 with Costello syndrome, cardiofaciocutaneous syndrome, NS with multiple lentigines, or NS with loose anagen hair. In summary, SOS2 is definitively associated with autosomal dominant Noonan syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 8/27/20 (SOP Version 7).

Noonan syndrome 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014691

Submitter: Labcorp Genetics (formerly Invitae)

Noonan syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018997

Submitter: Orphanet

Noonan syndrome 9DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014691

Submitter: Ambry Genetics

Noonan syndrome 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014691

Submitter: PanelApp Australia

Noonan syndrome 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014691

Submitter: Genomics England PanelApp

Noonan syndrome 9DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014691

Submitter: G2P

Clinical Genomic Database (CGD)

Noonan syndrome 9AD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Hematologic; Musculoskeletal; Neurologic

Intervention: Cardiovascular; Hematologic

Rationale: Surveillance and treatment related to manifestations such as cardiac anomalies (which include pulmonic stenosis) can be beneficial; The condition can include bleeding diathesis, and recognition and preventive measures (eg, in surgical situations) can be beneficial

Refs: 25795793

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SOS2 variants in ClinVar

14 Conditions Cataloged

Noonan syndrome 9Total: 1514

Cardiovascular phenotypeTotal: 699

not providedTotal: 331

not specifiedTotal: 268

SOS2-related disorderTotal: 103

Noonan syndrome and Noonan-related syndromeTotal: 22

Noonan syndromeTotal: 18

RASopathyTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006939.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	439 clinvar	3 clinvar	448
missense	5 clinvar	10 clinvar	869 clinvar	195 clinvar	6 clinvar	1085
nonsense			18 clinvar	1 clinvar		19
start loss			1 clinvar			1
frameshift			37 clinvar	1 clinvar		38
splice donor/acceptor (+/-2bp)			21 clinvar			21
Total	5	10	952	636	9	1612

Highest pathogenic variant AF is 0.0000013832196

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006939.4	RefSeq	NP_008870.2	23	MANE Select
ENST00000216373.10	Ensembl	ENSP00000216373.5	23	MANE Select
NM_001411020.1	RefSeq	NP_001397949.1	22	Standard
ENST00000543680.5	Ensembl	ENSP00000445328.1	22	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sos2	Danio rerio	Structure: pronephric proximal convoluted tubule Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

sos2

Danio rerio

Structure: pronephric proximal convoluted tubule

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Non-small cell lung cancer - Homo sapiens (human)
Chronic myeloid leukemia - Homo sapiens (human)
Gastric cancer - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)

Biological Process

G protein-coupled receptor signaling pathway
small GTPase mediated signal transduction
regulation of Rho protein signal transduction
positive regulation of apoptotic process
regulation of small GTPase mediated signal transduction

Molecular Function

DNA binding
guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
protein binding
protein heterodimerization activity

Cellular Component

nucleosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216373
Coding exons: 23
Length: 114430
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125748
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.53	506	693	0.730	0.0000356	8778
Missense (PolyPhen)		130	238.64	0.54475		3048
Synonymous	0.444	229	238	0.963	0.0000117	2488
Loss of Function	6.40	10	66.2	0.151	0.00000384	828

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000057	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.00011	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes the exchange of Ras-bound GDP by GTP. {ECO:0000250|UniProtKB:Q62245}.;
Disease: DISEASE: Noonan syndrome 9 (NS9) [MIM:616559]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:25795793}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.115

Intolerance Scores

LoFtool: 0.227
RVIS EVS: -0.93
RVIS percentile EVS: 9.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.757

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium