2-108768293-T-C

Position:

chr2-108768293-T-C

Variant summary

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

The NM_006267.5(RANBP2):c.7754T>C(p.Ile2585Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,612,030 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 42 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.59

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:

RANBP2 (HGNC:):

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=0.0031910837).

BP6

Variant 2-108768293-T-C is Benign according to our data. Variant chr2-108768293-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 380577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108768293-T-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 728 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.7754T>C	p.Ile2585Thr	missense_variant	20/29	ENST00000283195.11	NP_006258.3	P49792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11 linkuse as main transcript	c.7754T>C	p.Ile2585Thr	missense_variant	20/29	1	NM_006267.5	ENSP00000283195.6		P49792

Frequencies

GnomAD3 genomes

AF:

0.00478

AC:

728

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00695

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00453

AC:

1128

AN:

248980

Hom.:

AF XY:

0.00454

AC XY:

614

AN XY:

135270

show subpopulations

Gnomad AFR exome

AF:

0.000992

Gnomad AMR exome

AF:

0.00723

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00683

Gnomad OTH exome

AF:

0.00693

GnomAD4 exome

AF:

0.00622

AC:

9080

AN:

1459690

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

4423

AN XY:

726150

show subpopulations

Gnomad4 AFR exome

AF:

0.000898

Gnomad4 AMR exome

AF:

0.00718

Gnomad4 ASJ exome

AF:

0.000919

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000557

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.00740

Gnomad4 OTH exome

AF:

0.00550

GnomAD4 genome

AF:

0.00478

AC:

728

AN:

152340

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

356

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00139

Gnomad4 AMR

AF:

0.0102

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00695

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00477

Hom.:

Bravo

AF:

0.00544

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00643

AC:

ExAC

AF:

0.00443

AC:

537

EpiCase

AF:

0.00720

EpiControl

AF:

0.00824

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RANBP2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.0020

DANN

Benign

0.22

DEOGEN2

Benign

0.14

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0064

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.18

REVEL

Benign

0.054

Sift

Benign

0.68

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.039

MVP

0.14

MPC

0.44

ClinPred

0.00074

GERP RS

-10

Varity_R

0.015

gMVP

0.14

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