rs778281839

chr14-50150088-C-Achr14-50150088-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006939.4(SOS2):c.2304G>T(p.Gln768His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.85

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09084964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS2	NM_006939.4	c.2304G>T	p.Gln768His	missense_variant	14/23	ENST00000216373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.2304G>T	p.Gln768His	missense_variant	14/23	1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.2205G>T	p.Gln735His	missense_variant	13/22	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2021

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2023

The p.Q768H variant (also known as c.2304G>T), located in coding exon 14 of the SOS2 gene, results from a G to T substitution at nucleotide position 2304. The glutamine at codon 768 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	15
Dann	Benign	0.34
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.11
Sift	Benign	0.66	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0	B;.
Vest4		0.14
MutPred		0.32		Loss of sheet (P = 0.0457);.;
MVP		0.31
MPC		0.18
ClinPred		0.61	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.53

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: rs778281839; hg19: chr14-50616806;