rs61758802

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006267.5(RANBP2):c.2339C>T(p.Pro780Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00698 in 1,611,786 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P780P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 30)

Exomes 𝑓: 0.0072 ( 84 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.97

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070511103).

BP6

Variant 2-108755041-C-T is Benign according to our data. Variant chr2-108755041-C-T is described in ClinVar as Benign. ClinVar VariationId is 382461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00503 (765/152148) while in subpopulation SAS AF = 0.0211 (102/4824). AF 95% confidence interval is 0.0178. There are 4 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 765 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5 link	c.2339C>T	p.Pro780Leu	missense_variant	Exon 16 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.2339C>T	p.Pro780Leu	missense_variant	Exon 16 of 29	1	NM_006267.5	ENSP00000283195.6	P49792
RANBP2	ENST00000697737.1 link	c.2339C>T	p.Pro780Leu	missense_variant	Exon 16 of 27			ENSP00000513426.1	A0A8V8TL79
RANBP2	ENST00000697740.1 link	c.2261C>T	p.Pro754Leu	missense_variant	Exon 16 of 27			ENSP00000513427.1	A0A8V8TLA0

Frequencies

GnomAD3 genomes

AF:

0.00503

AC:

764

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.0202

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.000473

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00551

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00803

AC:

2008

AN:

250080

AF XY:

0.00825

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.00469

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.0266

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00537

Gnomad OTH exome

AF:

0.00806

GnomAD4 exome

AF:

0.00718

AC:

10487

AN:

1459638

Hom.:

Cov.:

AF XY:

0.00750

AC XY:

5449

AN XY:

726132

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33402

American (AMR)

AF:

0.00479

AC:

214

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00478

AC:

125

AN:

26128

East Asian (EAS)

AF:

0.0346

AC:

1372

AN:

39672

South Asian (SAS)

AF:

0.0201

AC:

1732

AN:

86164

European-Finnish (FIN)

AF:

0.000711

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00532

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00589

AC:

6554

AN:

1111804

Other (OTH)

AF:

0.00656

AC:

395

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

670

1341

2011

2682

3352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.00503

AC:

765

AN:

152148

Hom.:

Cov.:

AF XY:

0.00538

AC XY:

400

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41506

American (AMR)

AF:

0.00537

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.0203

AC:

105

AN:

5178

South Asian (SAS)

AF:

0.0211

AC:

102

AN:

4824

European-Finnish (FIN)

AF:

0.000473

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00552

AC:

375

AN:

67994

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00565

Hom.:

Bravo

AF:

0.00504

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00631

AC:

ExAC

AF:

0.00823

AC:

998

Asia WGS

AF:

0.0260

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 22, 2016

GeneDx

Significance: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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial acute necrotizing encephalopathy

Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Benign

-0.088

Eigen_PC

Benign

0.074

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

4.0

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.7

REVEL

Benign

0.11

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Polyphen

0.080

Vest4

0.23

MVP

0.30

MPC

1.1

ClinPred

0.039

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.53

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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