rs10658395

Positions:

Variant summary

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

The NM_006939.4(SOS2):c.3490-4del variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, 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]

SOS2 links:

Genome browser will be placed here

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/exons	MANE	Protein	UniProt
SOS2	NM_006939.4 linkuse as main transcript	c.3490-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10 linkuse as main transcript	c.3490-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006939.4	ENSP00000216373	P1	Q07890-1
SOS2	ENST00000543680.5 linkuse as main transcript	c.3391-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000445328		Q07890-2

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

142682

Hom.:

Cov.:

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.:

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.:

Cov.:

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:

AN:

142770

Hom.:

Cov.:

AF XY:

0.000637

AC XY:

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 submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 21, 2019

Variant 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 submitter

clinical testing

GeneDx

Sep 20, 2019

- -

SOS2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2019

This 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 submitter

clinical testing

Ambry Genetics

Nov 21, 2022

This 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 submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over