rs35396088

chr14-50182505-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006939.4(SOS2):c.816T>C(p.Ser272=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,613,700 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (75 hom., cov: 32)
  • Exomes 𝑓: 0.024 (570 hom.)
• Consequence: SOS2 NM_006939.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.199

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 14-50182505-A-G is Benign according to our data. Variant chr14-50182505-A-G is described in ClinVar as [Benign]. Clinvar id is 475762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50182505-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.199 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0205 (3120/152334) while in subpopulation NFE AF= 0.0258 (1756/68026). AF 95% confidence interval is 0.0248. There are 75 homozygotes in gnomad4. There are 1732 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3120 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS2	NM_006939.4	c.816T>C	p.Ser272=	synonymous_variant	6/23	ENST00000216373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.816T>C	p.Ser272=	synonymous_variant	6/23	1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.816T>C	p.Ser272=	synonymous_variant	6/22	1
SOS2	ENST00000556469.5	n.583T>C		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3120 AN: 152216 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0927

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0220 AC: 5525 AN: 251286 Hom.: 135 AF XY: 0.0220 AC XY: 2988 AN XY: 135790

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.0131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.0906

Gnomad NFE exome AF: 0.0264

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0236 AC: 34544 AN: 1461366 Hom.: 570 Cov.: 30 AF XY: 0.0231 AC XY: 16822 AN XY: 726998

Gnomad4 AFR exome AF: 0.00341

Gnomad4 AMR exome AF: 0.00588

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00208

Gnomad4 FIN exome AF: 0.0883

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome AF: 0.0205 AC: 3120 AN: 152334 Hom.: 75 Cov.: 32 AF XY: 0.0232 AC XY: 1732 AN XY: 74500

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0927

Gnomad4 NFE AF: 0.0258

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0216 Hom.: 22

Bravo AF: 0.0133

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0191

EpiControl AF: 0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 27, 2018	p.Ser272Ser in exon 6 of SOS2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 8.61% (568/6600) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs35396088). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2017	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Noonan syndrome 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided Benign:1

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.816T>C (p.Ser272Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2546/121094 control chromosomes at a frequency of 0.021025, which is approximately 8410 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2019

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

Jun 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	7.2
Dann	Benign	0.79

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: rs35396088; hg19: chr14-50649223;