14-50188639-G-T

Variant names:

• chr14-50188639-G-T
• rs72681869
• NM_006939.4:c.572C>A

Variant summary

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

The NM_006939.4(SOS2):​c.572C>A​(p.Pro191His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P191R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.572C>A	p.Pro191His	missense_variant	Exon 5 of 23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.572C>A	p.Pro191His	missense_variant	Exon 5 of 23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.572C>A	p.Pro191His	missense_variant	Exon 5 of 22	1		ENSP00000445328.1
SOS2	ENST00000556469.5	n.482-6033C>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

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

Mar 19, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SOS2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with histidine at codon 191 of the SOS2 protein (p.Pro191His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0050	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.81	P;.
Vest4		0.69
MutPred		0.22		Loss of glycosylation at P191 (P = 0.0565);Loss of glycosylation at P191 (P = 0.0565);
MVP		0.71
MPC		1.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.36
gMVP		0.42

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: rs72681869; hg19: chr14-50655357;