rs200438979

Positions:

chr2-108768344-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_006267.5(RANBP2):c.7805C>T(p.Thr2602Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,610,048 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00041 ( 2 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.47

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 -7 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=0.0142250955).

BS2

High AC in GnomAd4 at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.7805C>T	p.Thr2602Met	missense_variant	20/29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11 linkuse as main transcript	c.7805C>T	p.Thr2602Met	missense_variant	20/29	1	NM_006267.5	ENSP00000283195	P1

Frequencies

GnomAD3 genomes

AF:

0.000724

AC:

110

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00106

AC:

261

AN:

247298

Hom.:

AF XY:

0.00101

AC XY:

136

AN XY:

134574

show subpopulations

Gnomad AFR exome

AF:

0.000405

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.000301

Gnomad EAS exome

AF:

0.00125

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.00145

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.000407

AC:

593

AN:

1458064

Hom.:

Cov.:

AF XY:

0.000440

AC XY:

319

AN XY:

725398

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.000680

Gnomad4 SAS exome

AF:

0.000975

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000351

Gnomad4 OTH exome

AF:

0.000682

GnomAD4 genome

AF:

0.000724

AC:

110

AN:

151984

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00100

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00175

Hom.:

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000352

AC:

ExAC

AF:

0.00135

AC:

163

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial acute necrotizing encephalopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2602 of the RANBP2 protein (p.Thr2602Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RANBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 469489). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RANBP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.65

M_CAP

Benign

0.016

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.5

REVEL

Benign

0.050

Sift

Benign

0.22

Sift4G

Uncertain

0.026

Polyphen

0.66

Vest4

0.15

MVP

0.35

MPC

0.77

ClinPred

0.023

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.31

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