14-50188639-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006939.4(SOS2):c.572C>G(p.Pro191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,609,034 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0078 ( 55 hom. )

Consequence

SOS2
NM_006939.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 7.75

Variant links:

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]

SOS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011541516).

BP6

Variant 14-50188639-G-C is Benign according to our data. Variant chr14-50188639-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 445489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50188639-G-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 637 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 5 of 23	ENST00000216373.10	NP_008870.2	Q07890-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SOS2	ENST00000216373.10 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 5 of 23	1	NM_006939.4	ENSP00000216373.5	Q07890-1
SOS2	ENST00000543680.5 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 5 of 22	1		ENSP00000445328.1	Q07890-2
SOS2	ENST00000556469.5 link	n.482-6033C>G		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.00419

AC:

637

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00739

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00406

AC:

1011

AN:

248898

Hom.:

AF XY:

0.00413

AC XY:

556

AN XY:

134662

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.000699

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.000397

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.00746

Gnomad OTH exome

AF:

0.00477

GnomAD4 exome

AF:

0.00778

AC:

11340

AN:

1456788

Hom.:

Cov.:

AF XY:

0.00748

AC XY:

5422

AN XY:

724972

show subpopulations

Gnomad4 AFR exome

AF:

0.000781

Gnomad4 AMR exome

AF:

0.00241

Gnomad4 ASJ exome

AF:

0.000882

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000385

Gnomad4 FIN exome

AF:

0.00158

Gnomad4 NFE exome

AF:

0.00953

Gnomad4 OTH exome

AF:

0.00824

GnomAD4 genome

AF:

0.00418

AC:

637

AN:

152246

Hom.:

Cov.:

AF XY:

0.00378

AC XY:

281

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000661

Gnomad4 NFE

AF:

0.00739

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.00451

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00456

AC:

554

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00743

EpiControl

AF:

0.00783

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SOS2: BS1, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 17, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SOS2 c.572C>G (p.Pro191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 554/120618 control chromosomes (1 homozygote) at a frequency of 0.004593, which is approximately 1837 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 clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Noonan syndrome 9

Benign:4

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Jul 03, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 12, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Jun 03, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.35

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.52

Sift

Benign

0.068

T;T

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.36

B;.

Vest4

0.69

MVP

0.83

MPC

1.1

ClinPred

0.037

GERP RS

5.5

Varity_R

0.29

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over