rs145284139

Positions:

chr2-108765037-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The ENST00000283195.11(RANBP2):c.4498G>C(p.Ala1500Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,613,790 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

RANBP2
ENST00000283195.11 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter U:1B:3

Conservation

PhyloP100: 0.0640

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 -9 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=0.007832438).

BP6

Variant 2-108765037-G-C is Benign according to our data. Variant chr2-108765037-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 469460.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-108765037-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 183 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.4498G>C	p.Ala1500Pro	missense_variant	20/29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RANBP2	ENST00000283195.11 linkuse as main transcript	c.4498G>C	p.Ala1500Pro	missense_variant	20/29	1	NM_006267.5	ENSP00000283195	P1
RANBP2	ENST00000697737.1 linkuse as main transcript	c.2602+6489G>C		intron_variant				ENSP00000513426
RANBP2	ENST00000697740.1 linkuse as main transcript	c.2524+6489G>C		intron_variant				ENSP00000513427

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

182

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00416

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000402

AC:

101

AN:

251022

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.000984

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000119

AC:

174

AN:

1461756

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00305

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.00120

AC:

183

AN:

152034

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00417

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.00137

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000420

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

RANBP2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2024

The RANBP2 c.4498G>C variant is predicted to result in the amino acid substitution p.Ala1500Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.41% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial acute necrotizing encephalopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.21

M_CAP

Benign

0.038

MetaRNN

Benign

0.0078

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.4

REVEL

Benign

0.043

Sift

Benign

0.038

Sift4G

Benign

0.068

Polyphen

0.60

Vest4

0.15

MVP

0.41

MPC

1.1

ClinPred

0.021

GERP RS

2.4

Varity_R

0.13

gMVP

0.34

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