rs141604342

chr14-50159762-C-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006939.4(SOS2):c.1521G>T(p.Glu507Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,613,758 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.585

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074047744).
• BP6: Variant 14-50159762-C-A is Benign according to our data. Variant chr14-50159762-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 542411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS2	NM_006939.4	c.1521G>T	p.Glu507Asp	missense_variant	10/23	ENST00000216373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.1521G>T	p.Glu507Asp	missense_variant	10/23	1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.1422G>T	p.Glu474Asp	missense_variant	9/22	1
SOS2	ENST00000555794.2	c.636G>T	p.Glu212Asp	missense_variant	4/6	1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251168 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135756

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461474 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727054

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74446

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000366

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2019

- -

SOS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	6.0
Dann	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.20
Sift	Benign	0.23	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.012	B;.
Vest4		0.16
MutPred		0.43		Loss of ubiquitination at K502 (P = 0.0901);.;
MVP		0.51
MPC		0.54
ClinPred		0.037	T
GERP RS		-2.1
Varity_R		0.21
gMVP		0.30

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: rs141604342; hg19: chr14-50626480;