NM_012250.6:c.215A>G

Variant names:

• chr11-14294844-T-C
• rs113954997
• NM_012250.6:c.215A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_012250.6(RRAS2):​c.215A>G​(p.Gln72Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q72H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RRAS2 NM_012250.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.97
• Publications: 42 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: ClinGen, Orphanet
• noonan syndrome 12

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-14294844-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9447.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012250.6. 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
	RRAS2	NM_012250.6	MANE Select	c.215A>G	p.Gln72Arg	missense	Exon 3 of 6	NP_036382.2
	RRAS2	NM_001440708.1		c.215A>G	p.Gln72Arg	missense	Exon 3 of 7	NP_001427637.1
	RRAS2	NM_001177314.2		c.110A>G	p.Gln37Arg	missense	Exon 3 of 6	NP_001170785.1	P62070-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAS2	ENST00000256196.9	TSL:1 MANE Select	c.215A>G	p.Gln72Arg	missense	Exon 3 of 6	ENSP00000256196.4	P62070-1
	RRAS2	ENST00000526063.5	TSL:1	c.-17A>G		5_prime_UTR	Exon 3 of 6	ENSP00000434104.1	P62070-2
	RRAS2	ENST00000532814.5	TSL:1	c.-17A>G		5_prime_UTR	Exon 3 of 6	ENSP00000431954.1	P62070-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.85	P
Vest4		0.76
MutPred		0.76		Gain of methylation at Q72 (P = 0.0395)
MVP		0.97
MPC		1.2
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.72
Mutation Taster		=108/192	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: rs113954997; hg19: chr11-14316390;