Genetic Variant RRAS2:c.408+97_408+98dupAA (chr11-14294372-A-ATT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_012250.6(RRAS2):c.408+97_408+98dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 549,566 control chromosomes in the GnomAD database, including 15 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0075 ( 11 hom., cov: 0)

Exomes 𝑓: 0.028 ( 4 hom. )

Consequence

RRAS2
NM_012250.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.148

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 1127 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS2	NM_012250.6 link	c.408+97_408+98dupAA		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.408+98_408+99insAA		intron_variant	Intron 4 of 5	1	NM_012250.6	ENSP00000256196.4		P62070-1

Frequencies

GnomAD3 genomes

AF:

0.00750

AC:

1120

AN:

149386

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.0194

Gnomad EAS

AF:

0.00136

Gnomad SAS

AF:

0.00484

Gnomad FIN

AF:

0.000516

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.00644

Gnomad OTH

AF:

0.00492

GnomAD4 exome

AF:

0.0280

AC:

11192

AN:

400080

Hom.:

AF XY:

0.0285

AC XY:

5839

AN XY:

205146

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0267

AC:

281

AN:

10518

American (AMR)

AF:

0.0278

AC:

266

AN:

9578

Ashkenazi Jewish (ASJ)

AF:

0.0477

AC:

443

AN:

9282

East Asian (EAS)

AF:

0.0166

AC:

339

AN:

20444

South Asian (SAS)

AF:

0.0358

AC:

847

AN:

23666

European-Finnish (FIN)

AF:

0.0137

AC:

407

AN:

29624

Middle Eastern (MID)

AF:

0.0386

AC:

AN:

1476

European-Non Finnish (NFE)

AF:

0.0289

AC:

7961

AN:

275500

Other (OTH)

AF:

0.0296

AC:

591

AN:

19992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.299

Heterozygous variant carriers

1182

2363

3545

4726

5908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00754

AC:

1127

AN:

149486

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

523

AN XY:

72900

show subpopulations

African (AFR)

AF:

0.0116

AC:

476

AN:

40944

American (AMR)

AF:

0.00686

AC:

103

AN:

15012

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

AN:

3452

East Asian (EAS)

AF:

0.00137

AC:

AN:

5128

South Asian (SAS)

AF:

0.00464

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.000516

AC:

AN:

9694

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00645

AC:

434

AN:

67256

Other (OTH)

AF:

0.00487

AC:

AN:

2052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

106

158

211

264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00188

Hom.:

1792

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.15

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-14294372-ATTTT-ATTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over