chr19-49635628-G-C

Variant names:

• chr19-49635628-G-C
• rs2080992427
• NM_006270.5:c.605C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006270.5(RRAS):​c.605C>G​(p.Pro202Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000543 in 1,288,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. P202L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: RRAS NM_006270.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 0 publications found

Genes affected

RRAS (HGNC:10447): (RAS related) The protein encoded by this gene is a small GTPase involved in diverse processes including angiogenesis, vascular homeostasis and regeneration, cell adhesion, and neuronal axon guidance. Mutations in this gene are found in many invasive cancers. [provided by RefSeq, Jul 2015]

RRAS Gene-Disease associations (from GenCC):

• Noonan syndrome and Noonan-related syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Noonan syndrome

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, PanelApp Australia, ClinGen
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16003108).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006270.5. 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
	RRAS	NM_006270.5	MANE Select	c.605C>G	p.Pro202Arg	missense	Exon 6 of 6	NP_006261.1	P10301

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RRAS	ENST00000246792.4	TSL:1 MANE Select	c.605C>G	p.Pro202Arg	missense	Exon 6 of 6	ENSP00000246792.2	P10301
	RRAS	ENST00000962270.1		c.644C>G	p.Pro215Arg	missense	Exon 7 of 7	ENSP00000632329.1
	RRAS	ENST00000928399.1		c.614C>G	p.Pro205Arg	missense	Exon 6 of 6	ENSP00000598458.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000543 AC: 7 AN: 1288724 Hom.: 0 Cov.: 31 AF XY: 0.00000953 AC XY: 6 AN XY: 629702

African (AFR) AF: 0.00 AC: 0 AN: 27718

American (AMR) AF: 0.00 AC: 0 AN: 26082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18298

East Asian (EAS) AF: 0.00 AC: 0 AN: 33720

South Asian (SAS) AF: 0.00 AC: 0 AN: 60734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4946

European-Non Finnish (NFE) AF: 0.00000688 AC: 7 AN: 1017870

Other (OTH) AF: 0.00 AC: 0 AN: 51932

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.042
Sift	Benign	0.070	T
Sift4G	Benign	0.18	T
Polyphen		0.0060	B
Vest4		0.16
MutPred		0.33		Loss of glycosylation at P202 (P = 0.0041)
MVP		0.73
MPC		0.48
ClinPred		0.14	T
GERP RS		3.9
Varity_R		0.072
gMVP		0.41
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2080992427; hg19: chr19-50138885;