rs76352345

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006267.5(RANBP2):c.816G>C(p.Leu272Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,597,456 control chromosomes in the GnomAD database, including 594 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 63 hom., cov: 32)

Exomes 𝑓: 0.016 ( 531 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.531

Publications

13 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=0.0019601583).

BP6

Variant 2-108740522-G-C is Benign according to our data. Variant chr2-108740522-G-C is described in ClinVar as Benign. ClinVar VariationId is 381173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5 link	c.816G>C	p.Leu272Phe	missense_variant	Exon 7 of 29	ENST00000283195.11	NP_006258.3	P49792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11 link	c.816G>C	p.Leu272Phe	missense_variant	Exon 7 of 29	1	NM_006267.5	ENSP00000283195.6		P49792

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2100

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00786

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.0349

Gnomad SAS

AF:

0.0900

Gnomad FIN

AF:

0.0385

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0207

AC:

4948

AN:

238564

AF XY:

0.0238

show subpopulations

Gnomad AFR exome

AF:

0.00157

Gnomad AMR exome

AF:

0.00415

Gnomad ASJ exome

AF:

0.00561

Gnomad EAS exome

AF:

0.0323

Gnomad FIN exome

AF:

0.0349

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0161

AC:

23300

AN:

1445214

Hom.:

531

Cov.:

AF XY:

0.0180

AC XY:

12943

AN XY:

719326

show subpopulations

African (AFR)

AF:

0.00186

AC:

AN:

33402

American (AMR)

AF:

0.00528

AC:

236

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

128

AN:

26128

East Asian (EAS)

AF:

0.0353

AC:

1399

AN:

39682

South Asian (SAS)

AF:

0.0758

AC:

6529

AN:

86160

European-Finnish (FIN)

AF:

0.0330

AC:

1290

AN:

39144

Middle Eastern (MID)

AF:

0.00484

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0112

AC:

12429

AN:

1111736

Other (OTH)

AF:

0.0201

AC:

1207

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

1496

2992

4487

5983

7479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

546

1092

1638

2184

2730

<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:

0.0139

AC:

2120

AN:

152242

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1226

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

41538

American (AMR)

AF:

0.00785

AC:

120

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.0348

AC:

180

AN:

5178

South Asian (SAS)

AF:

0.0903

AC:

436

AN:

4828

European-Finnish (FIN)

AF:

0.0385

AC:

408

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

810

AN:

68022

Other (OTH)

AF:

0.0255

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

196

294

392

490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0145

Hom.:

Bravo

AF:

0.00913

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00293

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.0219

AC:

2612

Asia WGS

AF:

0.115

AC:

401

AN:

3478

EpiCase

AF:

0.00987

EpiControl

AF:

0.0105

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 14, 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. -

Familial acute necrotizing encephalopathy

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.53

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.0

REVEL

Benign

0.047

Sift

Benign

0.17

Sift4G

Pathogenic

0.0010

Polyphen

0.026

Vest4

0.050

MutPred

0.18

Loss of loop (P = 0.0112);

MPC

0.43

ClinPred

0.0018

GERP RS

0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.16

Mutation Taster

=98/2

polymorphism (auto)

(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