rs139387463

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_006267.5(RANBP2):c.9369+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,608,308 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

RANBP2
NM_006267.5 splice_region, intron

Scores

Splicing: ADA: 0.00007117

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.28

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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 2-108782866-G-A is Benign according to our data. Variant chr2-108782866-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5 link	c.9369+4G>A		splice_region_variant, intron_variant	Intron 28 of 28	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11 link	c.9369+4G>A		splice_region_variant, intron_variant	Intron 28 of 28	1	NM_006267.5	ENSP00000283195.6

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

164

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00112

AC:

276

AN:

247170

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00164

Gnomad NFE exome

AF:

0.00161

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.00182

AC:

2644

AN:

1456120

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1295

AN XY:

724800

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33396

American (AMR)

AF:

0.000313

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00180

AC:

155

AN:

86170

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

51186

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00210

AC:

2333

AN:

1108854

Other (OTH)

AF:

0.00108

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

118

235

353

470

588

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.00108

AC:

164

AN:

152188

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41512

American (AMR)

AF:

0.00137

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00165

AC:

112

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

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:

0.00148

Hom.:

Bravo

AF:

0.000937

EpiCase

AF:

0.00136

EpiControl

AF:

0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 12, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RANBP2: BS1, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial acute necrotizing encephalopathy

Benign:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000071

dbscSNV1_RF

Benign

0.032

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