NM_012250.6:c.409-16A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1BP4BP7

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

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: -2.13

Publications

15 publications found

Variant links:

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

RRAS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RRAS2	NM_012250.6 link	c.409-16A>T		intron_variant	Intron 4 of 5	ENST00000256196.9	NP_036382.2	P62070-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS2	ENST00000256196.9 link	c.409-16A>T		intron_variant	Intron 4 of 5	1	NM_012250.6	ENSP00000256196.4		P62070-1

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56281

AN:

151978

Hom.:

11569

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.421

AC:

97382

AN:

231122

AF XY:

0.421

show subpopulations

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 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.:

AF XY:

0.438

AC XY:

308190

AN XY:

703020

show subpopulations

African (AFR)

AF:

0.185

AC:

5852

AN:

31702

American (AMR)

AF:

0.600

AC:

23937

AN:

39914

Ashkenazi Jewish (ASJ)

AF:

0.423

AC:

10833

AN:

25590

East Asian (EAS)

AF:

0.314

AC:

11954

AN:

38082

South Asian (SAS)

AF:

0.419

AC:

33668

AN:

80380

European-Finnish (FIN)

AF:

0.321

AC:

17068

AN:

53176

Middle Eastern (MID)

AF:

0.431

AC:

2448

AN:

5680

European-Non Finnish (NFE)

AF:

0.454

AC:

488836

AN:

1077582

Other (OTH)

AF:

0.430

AC:

25233

AN:

58650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

16589

33177

49766

66354

82943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.370

AC:

56288

AN:

152096

Hom.:

11566

Cov.:

AF XY:

0.364

AC XY:

27082

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.198

AC:

8233

AN:

41494

American (AMR)

AF:

0.507

AC:

7749

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.428

AC:

1484

AN:

3466

East Asian (EAS)

AF:

0.319

AC:

1652

AN:

5174

South Asian (SAS)

AF:

0.408

AC:

1965

AN:

4820

European-Finnish (FIN)

AF:

0.310

AC:

3280

AN:

10570

Middle Eastern (MID)

AF:

0.418

AC:

123

AN:

294

European-Non Finnish (NFE)

AF:

0.448

AC:

30444

AN:

67980

Other (OTH)

AF:

0.408

AC:

861

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1736

3473

5209

6946

8682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 14, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome 12

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RASopathy

Benign:1

Sep 17, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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

(source)

DANN

Benign

0.74

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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NM_012250.6:c.409-16A>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over