NM_006506.5:c.17C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006506.5(RASA2):c.17C>T(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,392,716 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 25 hom. )

Consequence

RASA2
NM_006506.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -0.315

Publications

1 publications found

Variant links:

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

RASA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004214376).

BP6

Variant 3-141487100-C-T is Benign according to our data. Variant chr3-141487100-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218684.

BS2

High AC in GnomAd4 at 508 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASA2	NM_006506.5	MANE Select	c.17C>T	p.Pro6Leu	missense	Exon 1 of 24	NP_006497.2
RASA2	NM_001303246.3		c.17C>T	p.Pro6Leu	missense	Exon 1 of 25	NP_001290175.1
RASA2	NM_001303245.3		c.17C>T	p.Pro6Leu	missense	Exon 1 of 24	NP_001290174.1	Q15283-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASA2	ENST00000286364.9	TSL:1 MANE Select	c.17C>T	p.Pro6Leu	missense	Exon 1 of 24	ENSP00000286364.3	Q15283-2
RASA2	ENST00000930693.1		c.17C>T	p.Pro6Leu	missense	Exon 1 of 25	ENSP00000600752.1
RASA2	ENST00000950127.1		c.17C>T	p.Pro6Leu	missense	Exon 1 of 25	ENSP00000620186.1

Frequencies

GnomAD3 genomes

AF:

0.00338

AC:

509

AN:

150574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000920

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00231

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000805

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00613

Gnomad OTH

AF:

0.00290

GnomAD2 exomes

AF:

0.00357

AC:

281

AN:

78770

AF XY:

0.00317

show subpopulations

Gnomad AFR exome

AF:

0.000897

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.000191

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000727

Gnomad NFE exome

AF:

0.00784

Gnomad OTH exome

AF:

0.00460

GnomAD4 exome

AF:

0.00545

AC:

6773

AN:

1242034

Hom.:

Cov.:

AF XY:

0.00532

AC XY:

3252

AN XY:

611394

show subpopulations

African (AFR)

AF:

0.000716

AC:

AN:

25148

American (AMR)

AF:

0.00250

AC:

AN:

20428

Ashkenazi Jewish (ASJ)

AF:

0.000105

AC:

AN:

19058

East Asian (EAS)

AF:

0.00

AC:

AN:

25396

South Asian (SAS)

AF:

0.00192

AC:

122

AN:

63650

European-Finnish (FIN)

AF:

0.00101

AC:

AN:

43732

Middle Eastern (MID)

AF:

0.000858

AC:

AN:

3496

European-Non Finnish (NFE)

AF:

0.00634

AC:

6288

AN:

992372

Other (OTH)

AF:

0.00503

AC:

245

AN:

48754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

426

852

1277

1703

2129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00337

AC:

508

AN:

150682

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

216

AN XY:

73610

show subpopulations

African (AFR)

AF:

0.000918

AC:

AN:

41402

American (AMR)

AF:

0.00231

AC:

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000805

AC:

AN:

9940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00613

AC:

414

AN:

67492

Other (OTH)

AF:

0.00287

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00476

Hom.:

Bravo

AF:

0.00322

ESP6500AA

AF:

0.000741

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00152

AC:

149

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

RASA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.25

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.0

PhyloP100

-0.32

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.73

REVEL

Benign

0.11

Sift

Benign

0.18

Sift4G

Benign

0.24

Vest4

0.10

MVP

0.74

MPC

0.35

ClinPred

0.047

GERP RS

1.6

PromoterAI

0.053

Neutral

(source)

gMVP

0.35

Mutation Taster

=96/4

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over