rs61758802

Positions:

chr2-108755041-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_006267.5(RANBP2):c.2339C>T(p.Pro780Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00698 in 1,611,786 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 30)

Exomes 𝑓: 0.0072 ( 84 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.97

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=0.0070511103).

BP6

Variant 2-108755041-C-T is Benign according to our data. Variant chr2-108755041-C-T is described in ClinVar as [Benign]. Clinvar id is 382461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108755041-C-T is described in Lovd as [Benign]. Variant chr2-108755041-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00503 (765/152148) while in subpopulation SAS AF= 0.0211 (102/4824). AF 95% confidence interval is 0.0178. There are 4 homozygotes in gnomad4. There are 400 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 765 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.2339C>T	p.Pro780Leu	missense_variant	16/29	ENST00000283195.11	NP_006258.3	P49792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RANBP2	ENST00000283195.11 linkuse as main transcript	c.2339C>T	p.Pro780Leu	missense_variant	16/29	1	NM_006267.5	ENSP00000283195.6	P49792
RANBP2	ENST00000697737.1 linkuse as main transcript	c.2339C>T	p.Pro780Leu	missense_variant	16/27			ENSP00000513426.1	A0A8V8TL79
RANBP2	ENST00000697740.1 linkuse as main transcript	c.2261C>T	p.Pro754Leu	missense_variant	16/27			ENSP00000513427.1	A0A8V8TLA0

Frequencies

GnomAD3 genomes

AF:

0.00503

AC:

764

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.0202

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.000473

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00551

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00803

AC:

2008

AN:

250080

Hom.:

AF XY:

0.00825

AC XY:

1118

AN XY:

135552

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.00469

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.0266

Gnomad SAS exome

AF:

0.0200

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00537

Gnomad OTH exome

AF:

0.00806

GnomAD4 exome

AF:

0.00718

AC:

10487

AN:

1459638

Hom.:

Cov.:

AF XY:

0.00750

AC XY:

5449

AN XY:

726132

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00479

Gnomad4 ASJ exome

AF:

0.00478

Gnomad4 EAS exome

AF:

0.0346

Gnomad4 SAS exome

AF:

0.0201

Gnomad4 FIN exome

AF:

0.000711

Gnomad4 NFE exome

AF:

0.00589

Gnomad4 OTH exome

AF:

0.00656

GnomAD4 genome

AF:

0.00503

AC:

765

AN:

152148

Hom.:

Cov.:

AF XY:

0.00538

AC XY:

400

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.00537

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.0203

Gnomad4 SAS

AF:

0.0211

Gnomad4 FIN

AF:

0.000473

Gnomad4 NFE

AF:

0.00552

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00541

Hom.:

Bravo

AF:

0.00504

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00631

AC:

ExAC

AF:

0.00823

AC:

998

Asia WGS

AF:

0.0260

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial acute necrotizing encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Benign

-0.088

Eigen_PC

Benign

0.074

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.7

REVEL

Benign

0.11

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Polyphen

0.080

Vest4

0.23

MVP

0.30

MPC

1.1

ClinPred

0.039

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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