Genetic Variant NM_006939.4:c.496A>G (chr14-50199705-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006939.4(SOS2):c.496A>G(p.Met166Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SOS2
NM_006939.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Publications

0 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4 link	c.496A>G	p.Met166Val	missense_variant	Exon 4 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.496A>G	p.Met166Val	missense_variant	Exon 4 of 23	1	NM_006939.4	ENSP00000216373.5	Q07890-1
SOS2	ENST00000543680.5 link	c.496A>G	p.Met166Val	missense_variant	Exon 4 of 22	1		ENSP00000445328.1	Q07890-2
SOS2	ENST00000555666.1 link	n.675A>G		non_coding_transcript_exon_variant	Exon 4 of 4	4
SOS2	ENST00000556469.5 link	n.467A>G		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452234

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33034

American (AMR)

AF:

0.00

AC:

AN:

43180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26010

East Asian (EAS)

AF:

0.00

AC:

AN:

39344

South Asian (SAS)

AF:

0.00

AC:

AN:

84878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106706

Other (OTH)

AF:

0.00

AC:

AN:

59988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Noonan syndrome 9

Uncertain:1

May 19, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.064

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.85

L;L

PhyloP100

8.0

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.99

D;.

Vest4

0.87

MutPred

0.57

Loss of ubiquitination at K163 (P = 0.079);Loss of ubiquitination at K163 (P = 0.079);

MVP

0.77

MPC

1.5

ClinPred

0.97

GERP RS

4.8

Varity_R

0.50

gMVP

0.65

Mutation Taster

=51/49

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over