rs72681869

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006939.4(SOS2):​c.572C>T​(p.Pro191Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P191R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

SOS2
NM_006939.4 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.75

Publications

29 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SOS2NM_006939.4 linkc.572C>T p.Pro191Leu missense_variant Exon 5 of 23 ENST00000216373.10 NP_008870.2 Q07890-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SOS2ENST00000216373.10 linkc.572C>T p.Pro191Leu missense_variant Exon 5 of 23 1 NM_006939.4 ENSP00000216373.5 Q07890-1
SOS2ENST00000543680.5 linkc.572C>T p.Pro191Leu missense_variant Exon 5 of 22 1 ENSP00000445328.1 Q07890-2
SOS2ENST00000556469.5 linkn.482-6033C>T intron_variant Intron 4 of 4 3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.00000402
AC:
1
AN:
248898
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000549
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.00
Hom.:
4
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Sep 27, 2016
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The P191L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P191L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P191L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.63
D;.
Eigen
Benign
0.096
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Benign
0.040
D
MetaRNN
Uncertain
0.65
D;D
MetaSVM
Benign
-0.55
T
MutationAssessor
Uncertain
2.2
M;M
PhyloP100
7.8
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-4.0
D;D
REVEL
Uncertain
0.41
Sift
Benign
0.045
D;T
Sift4G
Pathogenic
0.0010
D;D
Polyphen
0.073
B;.
Vest4
0.71
MutPred
0.30
Loss of catalytic residue at P191 (P = 0.0352);Loss of catalytic residue at P191 (P = 0.0352);
MVP
0.75
MPC
0.62
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.22
gMVP
0.48
Mutation Taster
=74/26
polymorphism

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

Other links and lift over

dbSNP: rs72681869; hg19: chr14-50655357; API