rs869320687

Variant names:

• chr14-50161551-G-A
• NM_006939.4:c.1127C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-50161551-G-A
• chr14-50161551-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_006939.4(SOS2):​c.1127C>T​(p.Thr376Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T376S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain DH (size 190) in uniprot entity SOS2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006939.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50161551-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747
• PP5: Variant 14-50161551-G-A is Pathogenic according to our data. Variant chr14-50161551-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2821826.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.1127C>T	p.Thr376Ile	missense_variant	Exon 9 of 23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.1127C>T	p.Thr376Ile	missense_variant	Exon 9 of 23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.1028C>T	p.Thr343Ile	missense_variant	Exon 8 of 22	1		ENSP00000445328.1
SOS2	ENST00000555794.2	c.239C>T	p.Thr80Ile	missense_variant	Exon 3 of 6	1		ENSP00000484766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome 9 Pathogenic:1

Dec 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 376 of the SOS2 protein (p.Thr376Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS2 protein function. This variant disrupts the p.Thr376 amino acid residue in SOS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25795793, 26173643). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.60
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.078	T;T
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.55	P;.
Vest4		0.74
MutPred		0.45		Gain of catalytic residue at L381 (P = 0.048);.;
MVP		0.89
MPC		1.3
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.26
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50628269;