dbSNP rs760719711: RAP2A:p.Arg2His (chr13-97434475-G-A) – 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_021033.7(RAP2A):c.5G>A(p.Arg2His) variant causes a missense change. The variant allele was found at a frequency of 0.0000175 in 1,599,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

RAP2A
NM_021033.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.26

Publications

0 publications found

Variant links:

Genes affected

RAP2A (HGNC:9861): (RAP2A, member of RAS oncogene family) Enables GTPase activity; guanyl ribonucleotide binding activity; and magnesium ion binding activity. Involved in several processes, including actin cytoskeleton reorganization; microvillus assembly; and positive regulation of protein autophosphorylation. Acts upstream of or within establishment of protein localization. Located in plasma membrane and recycling endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

RAP2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAP2A	NM_021033.7 link	c.5G>A	p.Arg2His	missense_variant	Exon 1 of 2	ENST00000245304.5	NP_066361.1	P10114

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAP2A	ENST00000245304.5 link	c.5G>A	p.Arg2His	missense_variant	Exon 1 of 2	1	NM_021033.7	ENSP00000245304.3		P10114
RAP2A	ENST00000476869.1 link	n.5G>A		non_coding_transcript_exon_variant	Exon 1 of 3	3		ENSP00000436462.1		F6U784

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000166

AC:

AN:

241466

AF XY:

0.0000229

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1447954

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

718454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33198

American (AMR)

AF:

0.0000905

AC:

AN:

44184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25254

East Asian (EAS)

AF:

0.00

AC:

AN:

39368

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1103244

Other (OTH)

AF:

0.00

AC:

AN:

59678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151264

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73872

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41312

American (AMR)

AF:

0.00

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

67718

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000289

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 18, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5G>A (p.R2H) alteration is located in exon 1 (coding exon 1) of the RAP2A gene. This alteration results from a G to A substitution at nucleotide position 5, causing the arginine (R) at amino acid position 2 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.51

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.9

PhyloP100

5.3

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.55

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.030

Polyphen

1.0

Vest4

0.27

MutPred

0.35

Loss of MoRF binding (P = 0.0648);

MVP

0.81

MPC

2.7

ClinPred

0.79

GERP RS

2.9

PromoterAI

0.00050

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.86

Mutation Taster

=19/81

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over