rs76352345

Positions:

chr2-108740522-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 13/20 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:2

Conservation

PhyloP100: 0.531

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RANBP2. . Gene score misZ -0.77637 (greater than the threshold 3.09). Trascript score misZ 3.8106 (greater than threshold 3.09). GenCC has associacion of gene with Leigh syndrome, familial acute necrotizing encephalopathy.

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 id is 381173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108740522-G-C is described in Lovd as [Likely_benign].

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/exons	MANE	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.816G>C	p.Leu272Phe	missense_variant	7/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11 linkuse as main transcript	c.816G>C	p.Leu272Phe	missense_variant	7/29	1	NM_006267.5	P1

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

GnomAD3 exomes

AF:

0.0207

AC:

4948

AN:

238564

Hom.:

171

AF XY:

0.0238

AC XY:

3085

AN XY:

129852

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 SAS exome

AF:

0.0767

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

Gnomad4 AFR exome

AF:

0.00186

Gnomad4 AMR exome

AF:

0.00528

Gnomad4 ASJ exome

AF:

0.00490

Gnomad4 EAS exome

AF:

0.0353

Gnomad4 SAS exome

AF:

0.0758

Gnomad4 FIN exome

AF:

0.0330

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.0201

GnomAD4 genome

AF:

0.0139

AC:

2120

AN:

152242

Hom.:

Cov.:

AF XY:

0.0165

AC XY:

1226

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00217

Gnomad4 AMR

AF:

0.00785

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.0348

Gnomad4 SAS

AF:

0.0903

Gnomad4 FIN

AF:

0.0385

Gnomad4 NFE

AF:

0.0119

Gnomad4 OTH

AF:

0.0255

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

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

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

MutationTaster

Benign

1.0

N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over