rs138459515

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006939.4(SOS2):c.1868G>A(p.Arg623His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,605,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R623C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SOS2
NM_006939.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.66

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: Orphanet, ClinGen
Noonan syndrome 9
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SOS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.1868G>A	p.Arg623His	missense	Exon 11 of 23	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.1769G>A	p.Arg590His	missense	Exon 10 of 22	NP_001397949.1	Q07890-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOS2	ENST00000216373.10	TSL:1 MANE Select	c.1868G>A	p.Arg623His	missense	Exon 11 of 23	ENSP00000216373.5	Q07890-1
SOS2	ENST00000543680.5	TSL:1	c.1769G>A	p.Arg590His	missense	Exon 10 of 22	ENSP00000445328.1	Q07890-2
SOS2	ENST00000555794.2	TSL:1	c.980G>A	p.Arg327His	missense	Exon 5 of 6	ENSP00000484766.1	A0A087X277

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000887

AC:

AN:

247996

AF XY:

0.0000894

show subpopulations

Gnomad AFR exome

AF:

0.0000619

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:

0.000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000237

AC:

345

AN:

1453618

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

167

AN XY:

723558

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33190

American (AMR)

AF:

0.00

AC:

AN:

43762

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26000

East Asian (EAS)

AF:

0.00

AC:

AN:

39352

South Asian (SAS)

AF:

0.00

AC:

AN:

85362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.000307

AC:

340

AN:

1106826

Other (OTH)

AF:

0.0000833

AC:

AN:

60050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000921

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

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:

0.000115

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000548

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Noonan syndrome 9 (4)

SOS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.4

PhyloP100

7.7

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-4.4

REVEL

Uncertain

0.34

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0010

Polyphen

0.87

Vest4

0.84

MVP

0.64

MPC

1.7

ClinPred

0.90

GERP RS

4.5

Varity_R

0.69

gMVP

0.81

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over