11-14281736-T-A

Position:

• chr11-14281736-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The c.409-16A>T variant in RRAS2 is an intronic variant which is located in intron 4. It is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.6134 (97382/231122 alleles) in the Latino/Admixed American population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA5894276/MONDO:0021060/127

• Frequency:
  • Genomes: 𝑓 0.37 (11566 hom., cov: 32)
  • Exomes 𝑓: 0.44 (139238 hom.)
• Consequence: RRAS2 NM_012250.6 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -2.13

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RRAS2	NM_012250.6	c.409-16A>T		intron_variant		ENST00000256196.9	NP_036382.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RRAS2	ENST00000256196.9	c.409-16A>T		intron_variant		1	NM_012250.6	ENSP00000256196.4

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56281 AN: 151978 Hom.: 11569 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.310

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.408

GnomAD3 exomes AF: 0.421 AC: 97382 AN: 231122 Hom.: 22080 AF XY: 0.421 AC XY: 52757 AN XY: 125332

Gnomad AFR exome AF: 0.187

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.313

Gnomad SAS exome AF: 0.418

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.439

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.439 AC: 619829 AN: 1410756 Hom.: 139238 Cov.: 23 AF XY: 0.438 AC XY: 308190 AN XY: 703020

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.600

Gnomad4 ASJ exome AF: 0.423

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.430

GnomAD4 genome AF: 0.370 AC: 56288 AN: 152096 Hom.: 11566 Cov.: 32 AF XY: 0.364 AC XY: 27082 AN XY: 74344

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.507

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.310

Gnomad4 NFE AF: 0.448

Gnomad4 OTH AF: 0.408

Alfa AF: 0.326 Hom.: 1448

Bravo AF: 0.378

Asia WGS AF: 0.398 AC: 1381 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Noonan syndrome 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

RASopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Sep 17, 2024

The c.409-16A>T variant in RRAS2 is an intronic variant which is located in intron 4. It is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population filtering allele frequency in gnomAD v2.1.1 is 0.6134 (97382/231122 alleles) in the Latino/Admixed American population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.1; 9/17/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.7
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs2303972; hg19: chr11-14303282; COSMIC: COSV56329562;