rs1555367637

Positions:

• chr14-50118562-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006939.4(SOS2):​c.3781A>C​(p.Thr1261Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.03

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29827458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.3781A>C	p.Thr1261Pro	missense_variant	23/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.3781A>C	p.Thr1261Pro	missense_variant	23/23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.3682A>C	p.Thr1228Pro	missense_variant	22/22	1		ENSP00000445328.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2017

This sequence change replaces threonine with proline at codon 1261 of the SOS2 protein (p.Thr1261Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SOS2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.099	T;T
Sift4G	Benign	0.77	T;T
Polyphen		1.0	D;.
Vest4		0.39
MutPred		0.17		Loss of phosphorylation at T1261 (P = 0.0053);.;
MVP		0.58
MPC		0.63
ClinPred		0.87	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.12

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: rs1555367637; hg19: chr14-50585280;