rs753151750

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The c.3584C>T (NM_006939.4(SOS2):c.3584C>T (p.Ala1195Val)) variant in SOS2 is a missense variant predicted to cause substitution of alanine by valine at amino acid 1195. The filtering allele frequency in gnomAD v2.1.1 is 0.003446 % (no population codes met). The computational predictor REVEL gives a score of 0.183 which is below the threshold of 0.3, evidence that does not predict a damaging effect on SOS2 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (Version 2.3; 12/3/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7176746/MONDO:0021060/042

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

SOS2
NM_006939.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:3

Conservation

PhyloP100: 4.75

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Noonan syndrome 9
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P

SOS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4 link	c.3584C>T	p.Ala1195Val	missense_variant	Exon 23 of 23	ENST00000216373.10	NP_008870.2	Q07890-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10 link	c.3584C>T	p.Ala1195Val	missense_variant	Exon 23 of 23	1	NM_006939.4	ENSP00000216373.5		Q07890-1
SOS2	ENST00000543680.5 link	c.3485C>T	p.Ala1162Val	missense_variant	Exon 22 of 22	1		ENSP00000445328.1		Q07890-2

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151394

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000360

AC:

AN:

249676

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000710

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1460916

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1111384

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000396

AC:

AN:

151510

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41262

American (AMR)

AF:

0.00

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000210

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000736

AC:

AN:

67890

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000283

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 26, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SOS2: BP4 -

Cardiovascular phenotype

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A1195V variant (also known as c.3584C>T), located in coding exon 23 of the SOS2 gene, results from a C to T substitution at nucleotide position 3584. The alanine at codon 1195 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

RASopathy

Uncertain:1

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.3584C>T (NM_006939.4(SOS2):c.3584C>T (p.Ala1195Val)) variant in SOS2 is a missense variant predicted to cause substitution of alanine by valine at amino acid 1195. The filtering allele frequency in gnomAD v2.1.1 is 0.003446 % (no population codes met). The computational predictor REVEL gives a score of 0.183 which is below the threshold of 0.3, evidence that does not predict a damaging effect on SOS2 function (BP4). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal dominant RASopathy, based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BP4 (Version 2.3; 12/3/2024). -

Noonan syndrome 9

Benign:1

Oct 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.082

T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.0

N;.

PhyloP100

4.8

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.18

Sift

Benign

0.71

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0020

B;.

Vest4

0.038

MVP

0.16

MPC

0.19

ClinPred

0.15

GERP RS

5.0

Varity_R

0.078

gMVP

0.11

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over