11-14279356-C-G

Variant names:

• chr11-14279356-C-G
• rs1564950576
• NM_012250.6:c.596G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_012250.6(RRAS2):​c.596G>C​(p.Cys199Ser) 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 (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RRAS2 NM_012250.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86
• Publications: 1 publications found

Genes affected

RRAS2 (HGNC:17271): (RAS related 2) This gene encodes a member of the R-Ras subfamily of Ras-like small GTPases. The encoded protein associates with the plasma membrane and may function as a signal transducer. This protein may play an important role in activating signal transduction pathways that control cell proliferation. Mutations in this gene are associated with the growth of certain tumors. Pseudogenes of this gene are found on chromosomes 1 and 2. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RRAS2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• noonan syndrome 12

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

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a mutagenesis_site Does not affect lysine fatty-acylation. (size 0) in uniprot entity RRAS2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.7783 (below the threshold of 3.09). Trascript score misZ: 0.74497 (below the threshold of 3.09). GenCC associations: The gene is linked to noonan syndrome 12, Noonan syndrome, ovarian cancer.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS2	NM_012250.6	c.596G>C	p.Cys199Ser	missense_variant	Exon 6 of 6	ENST00000256196.9	NP_036382.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS2	ENST00000256196.9	c.596G>C	p.Cys199Ser	missense_variant	Exon 6 of 6	1	NM_012250.6	ENSP00000256196.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 15, 2022

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RRAS2 c.596G>C (p.Cys199Ser) missense variant results in the substitution of cysteine at amino acid position 199 with serine. To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.596G>C p.(Cys199Ser) variant is classified as a variant of uncertain significance for Noonan syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	.;.;.;D;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;.;.;D;.;.;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.3	.;.;.;L;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Benign	0.041	D;D;D;T;D;D;D
Sift4G	Uncertain	0.048	D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;D;.;.;.
Vest4		0.80
MutPred		0.37		.;.;.;Gain of phosphorylation at C199 (P = 0.0392);.;.;.;
MVP		0.62
MPC		1.1
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.40
gMVP		0.49
Mutation Taster		=16/84	disease causing

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: rs1564950576; hg19: chr11-14300902;