NM_006506.5:c.15_32dupGCCTGCTGCTGCGGCGGC

Variant names:

• chr3-141487089-G-GGCGGCGGCGCCTGCTGCT
• rs769524904
• NM_006506.5:c.15_32dupGCCTGCTGCTGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

The NM_006506.5(RASA2):​c.15_32dupGCCTGCTGCTGCGGCGGC​(p.Ala11_Ser12insProAlaAlaAlaAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,367,670 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: RASA2 NM_006506.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 0 publications found

Genes affected

RASA2 (HGNC:9872): (RAS p21 protein activator 2) The protein encoded by this gene is member of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

RASA2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006506.5.
• BS2: High AC in GnomAd4 at 25 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006506.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA2	NM_006506.5	MANE Select	c.15_32dupGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.15_32dupGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 25	NP_001290175.1
	RASA2	NM_001303245.3		c.15_32dupGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 24	NP_001290174.1	Q15283-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA2	ENST00000286364.9	TSL:1 MANE Select	c.15_32dupGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.15_32dupGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000600752.1
	RASA2	ENST00000950127.1		c.15_32dupGCCTGCTGCTGCGGCGGC	p.Ala11_Ser12insProAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes AF: 0.000166 AC: 25 AN: 150440 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000168 AC: 1 AN: 59442 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000800

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000353 AC: 43 AN: 1217120 Hom.: 0 Cov.: 30 AF XY: 0.0000301 AC XY: 18 AN XY: 597624

African (AFR) AF: 0.000871 AC: 21 AN: 24116

American (AMR) AF: 0.00 AC: 0 AN: 18272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17680

East Asian (EAS) AF: 0.0000413 AC: 1 AN: 24216

South Asian (SAS) AF: 0.00 AC: 0 AN: 60000

European-Finnish (FIN) AF: 0.000260 AC: 11 AN: 42300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3342

European-Non Finnish (NFE) AF: 0.00000817 AC: 8 AN: 979670

Other (OTH) AF: 0.0000421 AC: 2 AN: 47524

GnomAD4 genome AF: 0.000166 AC: 25 AN: 150550 Hom.: 0 Cov.: 32 AF XY: 0.000163 AC XY: 12 AN XY: 73550

African (AFR) AF: 0.000483 AC: 20 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000405 AC: 4 AN: 9884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67440

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=74/26	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs769524904; hg19: chr3-141205931;