rs61748146

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000283195.11(RANBP2):c.2330A>G(p.His777Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00392 in 1,611,920 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 119 hom., cov: 30)

Exomes 𝑓: 0.0022 ( 97 hom. )

Consequence

RANBP2
ENST00000283195.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.66

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=0.0028032362).

BP6

Variant 2-108755032-A-G is Benign according to our data. Variant chr2-108755032-A-G is described in ClinVar as [Benign]. Clinvar id is 383001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108755032-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.2330A>G	p.His777Arg	missense_variant	16/29	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.2330A>G	p.His777Arg	missense_variant	16/29	1	NM_006267.5	ENSP00000283195	P1
RANBP2	ENST00000697737.1 linkuse as main transcript	c.2330A>G	p.His777Arg	missense_variant	16/27			ENSP00000513426
RANBP2	ENST00000697740.1 linkuse as main transcript	c.2252A>G	p.His751Arg	missense_variant	16/27			ENSP00000513427

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3125

AN:

152170

Hom.:

119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0718

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00555

AC:

1388

AN:

249966

Hom.:

AF XY:

0.00446

AC XY:

605

AN XY:

135526

show subpopulations

Gnomad AFR exome

AF:

0.0760

Gnomad AMR exome

AF:

0.00283

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00278

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00297

GnomAD4 exome

AF:

0.00219

AC:

3193

AN:

1459632

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

1409

AN XY:

726126

show subpopulations

Gnomad4 AFR exome

AF:

0.0731

Gnomad4 AMR exome

AF:

0.00353

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00281

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.00483

GnomAD4 genome

AF:

0.0206

AC:

3130

AN:

152288

Hom.:

119

Cov.:

AF XY:

0.0199

AC XY:

1479

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0717

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00173

Hom.:

Bravo

AF:

0.0228

ESP6500AA

AF:

0.0674

AC:

296

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00702

AC:

851

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Jun 06, 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

Jan 18, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.79

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.11

Sift

Uncertain

0.027

Sift4G

Uncertain

0.010

Polyphen

0.61

Vest4

0.40

MVP

0.43

MPC

1.3

ClinPred

0.029

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.30

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