rs187011794

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006267.5(RANBP2):c.2405G>A(p.Arg802Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00049 in 1,611,674 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R802R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 30)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.24

Publications

3 publications found

Variant links:

Genes affected

RANBP2 (HGNC:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

RANBP2 Gene-Disease associations (from GenCC):

familial acute necrotizing encephalopathy
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008634537).

BP6

Variant 2-108755198-G-A is Benign according to our data. Variant chr2-108755198-G-A is described in ClinVar as Benign. ClinVar VariationId is 537231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5 link	c.2405G>A	p.Arg802Gln	missense_variant	Exon 17 of 29	ENST00000283195.11	NP_006258.3	P49792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RANBP2	ENST00000283195.11 link	c.2405G>A	p.Arg802Gln	missense_variant	Exon 17 of 29	1	NM_006267.5	ENSP00000283195.6	P49792
RANBP2	ENST00000697737.1 link	c.2405G>A	p.Arg802Gln	missense_variant	Exon 17 of 27			ENSP00000513426.1	A0A8V8TL79
RANBP2	ENST00000697740.1 link	c.2327G>A	p.Arg776Gln	missense_variant	Exon 17 of 27			ENSP00000513427.1	A0A8V8TLA0

Frequencies

GnomAD3 genomes

AF:

0.000435

AC:

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00560

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.000379

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000699

AC:

175

AN:

250234

AF XY:

0.000649

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00593

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.000345

Gnomad OTH exome

AF:

0.00132

GnomAD4 exome

AF:

0.000495

AC:

723

AN:

1459690

Hom.:

Cov.:

AF XY:

0.000489

AC XY:

355

AN XY:

726146

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33406

American (AMR)

AF:

0.000335

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00448

AC:

178

AN:

39690

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.000655

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.000398

AC:

442

AN:

1111832

Other (OTH)

AF:

0.000781

AC:

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

134

178

223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000434

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41434

American (AMR)

AF:

0.000262

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00561

AC:

AN:

5168

South Asian (SAS)

AF:

0.000416

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.000379

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

67976

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000293

Hom.:

Bravo

AF:

0.000548

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000808

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial acute necrotizing encephalopathy

Benign:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RANBP2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.20

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.80

M_CAP

Benign

0.0031

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.81

PhyloP100

1.2

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.85

REVEL

Benign

0.050

Sift

Benign

0.19

Sift4G

Benign

0.96

Polyphen

0.070

Vest4

0.21

MVP

0.31

MPC

1.2

ClinPred

0.0099

GERP RS

1.0

Varity_R

0.032

gMVP

0.25

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over