rs776380363

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_006267.5(RANBP2):c.4999G>A(p.Gly1667Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000532 in 1,560,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 11)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.55

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

BS2

High AC in GnomAd4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006267.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RANBP2	NM_006267.5	MANE Select	c.4999G>A	p.Gly1667Arg	missense	Exon 20 of 29	NP_006258.3
RANBP2	NM_001415871.1		c.4999G>A	p.Gly1667Arg	missense	Exon 20 of 30	NP_001402800.1
RANBP2	NM_001415873.1		c.4999G>A	p.Gly1667Arg	missense	Exon 20 of 29	NP_001402802.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.4999G>A	p.Gly1667Arg	missense	Exon 20 of 29	ENSP00000283195.6
RANBP2	ENST00000697737.1		c.2603-6163G>A		intron	N/A	ENSP00000513426.1
RANBP2	ENST00000697740.1		c.2525-6163G>A		intron	N/A	ENSP00000513427.1

Frequencies

GnomAD3 genomes

AF:

0.000110

AC:

AN:

100290

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000397

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000951

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000202

AC:

AN:

247108

AF XY:

0.00000745

show subpopulations

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:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1460360

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.0000750

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

1110678

Other (OTH)

AF:

0.0000166

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.000110

AC:

AN:

100290

Hom.:

Cov.:

AF XY:

0.0000829

AC XY:

AN XY:

48234

show subpopulations

African (AFR)

AF:

0.0000397

AC:

AN:

25166

American (AMR)

AF:

0.0000951

AC:

AN:

10514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2560

East Asian (EAS)

AF:

0.00

AC:

AN:

3346

South Asian (SAS)

AF:

0.00

AC:

AN:

2180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

47162

Other (OTH)

AF:

0.00

AC:

AN:

1176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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:

0.00

Hom.:

ExAC

AF:

0.0000587

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Familial acute necrotizing encephalopathy (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

3.8

PhyloP100

5.6

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.62

Sift

Uncertain

0.010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.66

MutPred

0.75

Gain of MoRF binding (P = 0.0125)

MVP

0.83

MPC

0.43

ClinPred

0.53

GERP RS

3.5

Varity_R

0.13

gMVP

0.27

Mutation Taster

=54/46

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over