rs17122201

Positions:

• chr14-50159835-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000216373.10(SOS2):​c.1448G>A​(p.Ser483Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,614,066 control chromosomes in the GnomAD database, including 284 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (144 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (140 hom.)
• Consequence: SOS2 ENST00000216373.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.280

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011952221).
• BP6: Variant 14-50159835-C-T is Benign according to our data. Variant chr14-50159835-C-T is described in ClinVar as [Benign]. Clinvar id is 388232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0806 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.1448G>A	p.Ser483Asn	missense_variant	10/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.1448G>A	p.Ser483Asn	missense_variant	10/23	1	NM_006939.4	ENSP00000216373	P1
SOS2	ENST00000543680.5	c.1349G>A	p.Ser450Asn	missense_variant	9/22	1		ENSP00000445328
SOS2	ENST00000555794.2	c.563G>A	p.Ser188Asn	missense_variant	4/6	1		ENSP00000484766

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3695 AN: 152098 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0828

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00707 AC: 1777 AN: 251358 Hom.: 67 AF XY: 0.00526 AC XY: 714 AN XY: 135848

Gnomad AFR exome AF: 0.0882

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00290 AC: 4237 AN: 1461850 Hom.: 140 Cov.: 32 AF XY: 0.00254 AC XY: 1846 AN XY: 727226

Gnomad4 AFR exome AF: 0.0851

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000429

Gnomad4 OTH exome AF: 0.00732

GnomAD4 genome AF: 0.0244 AC: 3707 AN: 152216 Hom.: 144 Cov.: 32 AF XY: 0.0232 AC XY: 1729 AN XY: 74418

Gnomad4 AFR AF: 0.0829

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00647 Hom.: 50

Bravo AF: 0.0276

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0803 AC: 354

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00848 AC: 1030

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2017	Variant summary: The SOS2 c.1448G>A (p.Ser483Asn) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution. The variant lies within the Pleckstrin homology domain (InterPro) and 4/4 in silico tools predict a benign outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0084862 in all populations (1030/121374 control chromosomes [39 homozygotes]), but was observed most commonly in the African subpopulation at a frequency of 0.087794 (912/10388 [38 homozygotes]). This frequency is about 35118 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), providing strong evidence that this is likely a benign polymorphism found primarily in the populations of African origin. One publication has reported the variant in 6 individuals diagnosed with RASopathies or Noonan syndrome. However, co-segregation data was not provided and the authors classified the variant as a polymorphism (Cordeddu_HM_2015). In addition, one clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

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

Mar 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.19
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.5	N;.
MutationTaster	Benign	0.86	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.12
MVP		0.16
MPC		0.55
ClinPred		0.00072	T
GERP RS		1.3
Varity_R		0.026
gMVP		0.096

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs17122201; hg19: chr14-50626553;