rs10658395

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_006939.4(SOS2):​c.3490-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,174,898 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0013 ( 13 hom. )

Consequence

SOS2
NM_006939.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.39
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 14-50118856-CA-C is Benign according to our data. Variant chr14-50118856-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 706888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50118856-CA-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00129 (1336/1032128) while in subpopulation SAS AF= 0.019 (625/32922). AF 95% confidence interval is 0.0178. There are 13 homozygotes in gnomad4_exome. There are 745 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.
BS2
High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SOS2NM_006939.4 linkc.3490-4delT splice_region_variant, intron_variant Intron 22 of 22 ENST00000216373.10 NP_008870.2 Q07890-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SOS2ENST00000216373.10 linkc.3490-4delT splice_region_variant, intron_variant Intron 22 of 22 1 NM_006939.4 ENSP00000216373.5 Q07890-1
SOS2ENST00000543680.5 linkc.3391-4delT splice_region_variant, intron_variant Intron 21 of 21 1 ENSP00000445328.1 Q07890-2

Frequencies

GnomAD3 genomes
AF:
0.000512
AC:
73
AN:
142682
Hom.:
0
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.000212
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000700
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000415
Gnomad SAS
AF:
0.0137
Gnomad FIN
AF:
0.000112
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000152
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00342
AC:
355
AN:
103896
Hom.:
2
AF XY:
0.00399
AC XY:
227
AN XY:
56850
show subpopulations
Gnomad AFR exome
AF:
0.00395
Gnomad AMR exome
AF:
0.00210
Gnomad ASJ exome
AF:
0.00379
Gnomad EAS exome
AF:
0.00305
Gnomad SAS exome
AF:
0.0206
Gnomad FIN exome
AF:
0.00153
Gnomad NFE exome
AF:
0.00154
Gnomad OTH exome
AF:
0.00429
GnomAD4 exome
AF:
0.00129
AC:
1336
AN:
1032128
Hom.:
13
Cov.:
24
AF XY:
0.00149
AC XY:
745
AN XY:
499010
show subpopulations
Gnomad4 AFR exome
AF:
0.00134
Gnomad4 AMR exome
AF:
0.000991
Gnomad4 ASJ exome
AF:
0.000426
Gnomad4 EAS exome
AF:
0.000909
Gnomad4 SAS exome
AF:
0.0190
Gnomad4 FIN exome
AF:
0.00126
Gnomad4 NFE exome
AF:
0.000618
Gnomad4 OTH exome
AF:
0.00147
GnomAD4 genome
AF:
0.000504
AC:
72
AN:
142770
Hom.:
0
Cov.:
0
AF XY:
0.000637
AC XY:
44
AN XY:
69026
show subpopulations
Gnomad4 AFR
AF:
0.000211
Gnomad4 AMR
AF:
0.0000700
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000416
Gnomad4 SAS
AF:
0.0135
Gnomad4 FIN
AF:
0.000112
Gnomad4 NFE
AF:
0.0000152
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Noonan syndrome 9 Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2025- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 19, 2023- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou Lab-- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 21, 2019Variant summary: SOS2 c.3490-4delT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 103896 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1367 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3490-4delT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxSep 20, 2019- -
SOS2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 25, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 21, 2022This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenApr 09, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.24
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.24
Position offset: -3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs10658395; hg19: chr14-50585574; API