rs777684425

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_006939.4(SOS2):c.3338-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000063 in 1,428,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

SOS2
NM_006939.4 splice_region, intron

Scores

Splicing: ADA: 0.9959

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.886

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:

ENSG00000308262 (HGNC:):

ENSG00000308262 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4 link	c.3338-4A>G		splice_region_variant, intron_variant	Intron 20 of 22	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SOS2	ENST00000216373.10 link	c.3338-4A>G	splice_region_variant, intron_variant	Intron 20 of 22	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5 link	c.3239-4A>G	splice_region_variant, intron_variant	Intron 19 of 21	1		ENSP00000445328.1
ENSG00000308262	ENST00000832887.1 link	n.*107A>G	downstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000165

AC:

AN:

242210

AF XY:

0.0000153

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:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000630

AC:

AN:

1428486

Hom.:

Cov.:

AF XY:

0.00000562

AC XY:

AN XY:

712054

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32618

American (AMR)

AF:

0.00

AC:

AN:

42816

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25708

East Asian (EAS)

AF:

0.00

AC:

AN:

39252

South Asian (SAS)

AF:

0.0000240

AC:

AN:

83204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00000552

AC:

AN:

1086796

Other (OTH)

AF:

0.00

AC:

AN:

59196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Noonan syndrome 9

Uncertain:1

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 20 of the SOS2 gene. It does not directly change the encoded amino acid sequence of the SOS2 protein. This variant is present in population databases (rs777684425, gnomAD 0.007%). This variant has been observed in individual(s) with SOS2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 542397). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: -1

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over