11-14279213-C-G

Variant names:

• chr11-14279213-C-G
• rs8570
• NM_012250.6:c.*124G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012250.6(RRAS2):​c.*124G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 697,882 control chromosomes in the GnomAD database, including 32,979 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6172 hom., cov: 31)
  • Exomes 𝑓: 0.30 (26807 hom.)
• Consequence: RRAS2 NM_012250.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.76
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-14279213-C-G is Benign according to our data. Variant chr11-14279213-C-G is described in ClinVar as [Benign]. Clinvar id is 1288635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS2	NM_012250.6	c.*124G>C		3_prime_UTR_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.*124G>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_012250.6	ENSP00000256196.4

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40665 AN: 151782 Hom.: 6170 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.300 AC: 163828 AN: 545982 Hom.: 26807 Cov.: 7 AF XY: 0.302 AC XY: 87720 AN XY: 290602

African (AFR) AF: 0.103 AC: 1543 AN: 14996

American (AMR) AF: 0.197 AC: 5241 AN: 26610

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 5598 AN: 15752

East Asian (EAS) AF: 0.401 AC: 13102 AN: 32678

South Asian (SAS) AF: 0.330 AC: 17047 AN: 51586

European-Finnish (FIN) AF: 0.348 AC: 15938 AN: 45818

Middle Eastern (MID) AF: 0.324 AC: 704 AN: 2170

European-Non Finnish (NFE) AF: 0.294 AC: 96109 AN: 327264

Other (OTH) AF: 0.294 AC: 8546 AN: 29108

GnomAD4 genome AF: 0.268 AC: 40690 AN: 151900 Hom.: 6172 Cov.: 31 AF XY: 0.274 AC XY: 20307 AN XY: 74204

African (AFR) AF: 0.115 AC: 4788 AN: 41474

American (AMR) AF: 0.259 AC: 3946 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1347 AN: 3464

East Asian (EAS) AF: 0.374 AC: 1936 AN: 5170

South Asian (SAS) AF: 0.367 AC: 1765 AN: 4806

European-Finnish (FIN) AF: 0.369 AC: 3878 AN: 10498

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22081 AN: 67946

Other (OTH) AF: 0.269 AC: 566 AN: 2106

Alfa AF: 0.173 Hom.: 378

Bravo AF: 0.252

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.3
DANN	Benign	0.82
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs8570; hg19: chr11-14300759; COSMIC: COSV56330314; COSMIC: COSV56330314;