NM_006506.5:c.15_32delGCCTGCTGCTGCGGCGGC

Variant names:

• chr3-141487089-GGCGGCGGCGCCTGCTGCT-G
• rs769524904
• NM_006506.5:c.15_32delGCCTGCTGCTGCGGCGGC

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_32delGCCTGCTGCTGCGGCGGC​(p.Pro6_Ala11del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000951 in 1,367,560 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: RASA2 NM_006506.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• 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 GnomAdExome4 at 12 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_32delGCCTGCTGCTGCGGCGGC	p.Pro6_Ala11del	disruptive_inframe_deletion	Exon 1 of 24	NP_006497.2
	RASA2	NM_001303246.3		c.15_32delGCCTGCTGCTGCGGCGGC	p.Pro6_Ala11del	disruptive_inframe_deletion	Exon 1 of 25	NP_001290175.1
	RASA2	NM_001303245.3		c.15_32delGCCTGCTGCTGCGGCGGC	p.Pro6_Ala11del	disruptive_inframe_deletion	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_32delGCCTGCTGCTGCGGCGGC	p.Pro6_Ala11del	disruptive_inframe_deletion	Exon 1 of 24	ENSP00000286364.3	Q15283-2
	RASA2	ENST00000930693.1		c.15_32delGCCTGCTGCTGCGGCGGC	p.Pro6_Ala11del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000600752.1
	RASA2	ENST00000950127.1		c.15_32delGCCTGCTGCTGCGGCGGC	p.Pro6_Ala11del	disruptive_inframe_deletion	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150440 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

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: 0.0000300

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000986 AC: 12 AN: 1217120 Hom.: 0 AF XY: 0.0000100 AC XY: 6 AN XY: 597624

African (AFR) AF: 0.000166 AC: 4 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: 0.0000333 AC: 2 AN: 60000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42302

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

European-Non Finnish (NFE) AF: 0.00000408 AC: 4 AN: 979668

Other (OTH) AF: 0.0000210 AC: 1 AN: 47524

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150440 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73430

African (AFR) AF: 0.0000242 AC: 1 AN: 41262

American (AMR) AF: 0.00 AC: 0 AN: 15108

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67450

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=184/16	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;