NM_012250.6:c.408+102G>A

Variant names:

• chr11-14294369-C-T
• rs34238445
• NM_012250.6:c.408+102G>A

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.408+102G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 685,742 control chromosomes in the GnomAD database, including 38,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (6122 hom., cov: 31)
  • Exomes 𝑓: 0.33 (32240 hom.)
• Consequence: RRAS2 NM_012250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.566
• Publications: 1 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=-0.86).
• BP6: Variant 11-14294369-C-T is Benign according to our data. Variant chr11-14294369-C-T is described in ClinVar as [Benign]. Clinvar id is 1238516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAS2	NM_012250.6	c.408+102G>A		intron_variant	Intron 4 of 5	ENST00000256196.9	NP_036382.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAS2	ENST00000256196.9	c.408+102G>A		intron_variant	Intron 4 of 5	1	NM_012250.6	ENSP00000256196.4

Frequencies

GnomAD3 genomes AF: 0.395 AC: 40246 AN: 101854 Hom.: 6123 Cov.: 31

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.464

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.400

GnomAD4 exome AF: 0.327 AC: 190913 AN: 583810 Hom.: 32240 AF XY: 0.329 AC XY: 98963 AN XY: 300928

African (AFR) AF: 0.101 AC: 1374 AN: 13660

American (AMR) AF: 0.247 AC: 3658 AN: 14808

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 5520 AN: 14176

East Asian (EAS) AF: 0.415 AC: 12596 AN: 30364

South Asian (SAS) AF: 0.353 AC: 13093 AN: 37052

European-Finnish (FIN) AF: 0.366 AC: 16194 AN: 44270

Middle Eastern (MID) AF: 0.335 AC: 753 AN: 2246

European-Non Finnish (NFE) AF: 0.323 AC: 128446 AN: 397746

Other (OTH) AF: 0.315 AC: 9279 AN: 29488

GnomAD4 genome AF: 0.395 AC: 40253 AN: 101932 Hom.: 6122 Cov.: 31 AF XY: 0.403 AC XY: 20114 AN XY: 49884

African (AFR) AF: 0.171 AC: 4385 AN: 25630

American (AMR) AF: 0.432 AC: 3948 AN: 9142

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1348 AN: 2542

East Asian (EAS) AF: 0.494 AC: 1937 AN: 3918

South Asian (SAS) AF: 0.510 AC: 1753 AN: 3436

European-Finnish (FIN) AF: 0.530 AC: 3847 AN: 7256

Middle Eastern (MID) AF: 0.449 AC: 96 AN: 214

European-Non Finnish (NFE) AF: 0.462 AC: 22087 AN: 47786

Other (OTH) AF: 0.404 AC: 562 AN: 1392

Alfa AF: 0.303 Hom.: 9577

Bravo AF: 0.249

Asia WGS AF: 0.327 AC: 1120 AN: 3422

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.16
DANN	Benign	0.91
PhyloP100		-0.57
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: rs34238445; hg19: chr11-14315915; COSMIC: COSV56329685; COSMIC: COSV56329685;