rs111961549

Positions:

• chr14-50161607-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_006939.4(SOS2):​c.1071A>G​(p.Gln357Gln) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,609,548 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (2 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.03

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 -12 ACMG points.

• BP6: Variant 14-50161607-T-C is Benign according to our data. Variant chr14-50161607-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.1071A>G	p.Gln357Gln	splice_region_variant, synonymous_variant	9/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.1071A>G	p.Gln357Gln	splice_region_variant, synonymous_variant	9/23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.972A>G	p.Gln324Gln	splice_region_variant, synonymous_variant	8/22	1		ENSP00000445328.1
SOS2	ENST00000555794.2	c.183A>G	p.Gln61Gln	splice_region_variant, synonymous_variant	3/6	1		ENSP00000484766.1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000338 AC: 83 AN: 245800 Hom.: 0 AF XY: 0.000384 AC XY: 51 AN XY: 132742

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000603

Gnomad ASJ exome AF: 0.000607

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000888 AC: 1294 AN: 1457422 Hom.: 2 Cov.: 29 AF XY: 0.000846 AC XY: 613 AN XY: 724822

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74306

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000638 Hom.: 0

Bravo AF: 0.000431

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	SOS2: PP3, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Aug 20, 2022

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2019

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs111961549; hg19: chr14-50628325;