14-50150088-C-A

Variant names:

• chr14-50150088-C-A
• rs778281839
• NM_006939.4:c.2304G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 in silico tools predict a benign outcome for this variant. 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. Q768P) has been classified 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
• Publications: 1 publications found

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]

SOS2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.2304G>T	p.Gln768His	missense	Exon 14 of 23	NP_008870.2
	SOS2	NM_001411020.1		c.2205G>T	p.Gln735His	missense	Exon 13 of 22	NP_001397949.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.2304G>T	p.Gln768His	missense	Exon 14 of 23	ENSP00000216373.5
	SOS2	ENST00000543680.5	TSL:1	c.2205G>T	p.Gln735His	missense	Exon 13 of 22	ENSP00000445328.1
	SOS2	ENST00000934708.1		c.2445G>T	p.Gln815His	missense	Exon 15 of 24	ENSP00000604767.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Noonan syndrome 9 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		1.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Benign	0.66	T
Sift4G	Benign	0.60	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
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs778281839; hg19: chr14-50616806;