rs61748150

Positions:

chr2-108766480-T-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_006267.5(RANBP2):c.5941T>A(p.Ser1981Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0122 in 1,611,950 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 5 hom., cov: 32)

Exomes 𝑓: 0.013 ( 143 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.20

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 -15 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=0.008125693).

BP6

Variant 2-108766480-T-A is Benign according to our data. Variant chr2-108766480-T-A is described in ClinVar as [Benign]. Clinvar id is 380579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108766480-T-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 1234 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.5941T>A	p.Ser1981Thr	missense_variant	20/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11 linkuse as main transcript	c.5941T>A	p.Ser1981Thr	missense_variant	20/29	1	NM_006267.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00811

AC:

1234

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00825

AC:

2044

AN:

247792

Hom.:

AF XY:

0.00832

AC XY:

1122

AN XY:

134836

show subpopulations

Gnomad AFR exome

AF:

0.00184

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.0147

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.00679

GnomAD4 exome

AF:

0.0126

AC:

18409

AN:

1459692

Hom.:

143

Cov.:

AF XY:

0.0122

AC XY:

8827

AN XY:

726152

show subpopulations

Gnomad4 AFR exome

AF:

0.00165

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.0157

Gnomad4 NFE exome

AF:

0.0151

Gnomad4 OTH exome

AF:

0.00982

GnomAD4 genome

AF:

0.00810

AC:

1234

AN:

152258

Hom.:

Cov.:

AF XY:

0.00764

AC XY:

569

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00286

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0151

Gnomad4 NFE

AF:

0.0130

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00960

Hom.:

Bravo

AF:

0.00727

ESP6500AA

AF:

0.00268

AC:

ESP6500EA

AF:

0.0133

AC:

110

ExAC

AF:

0.00890

AC:

1069

EpiCase

AF:

0.0121

EpiControl

AF:

0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 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

Dec 18, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

RANBP2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.39

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0081

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.96

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.5

REVEL

Benign

0.098

Sift

Benign

0.33

Sift4G

Pathogenic

0.0010

Polyphen

0.39

Vest4

0.18

MVP

0.58

MPC

0.38

ClinPred

0.018

GERP RS

5.8

Varity_R

0.18

gMVP

0.27

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