2-108730858-C-G

Position:

chr2-108730858-C-G

Variant summary

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

The NM_006267.5(RANBP2):c.225C>G(p.Asn75Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,611,624 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 2 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.277

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 -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=0.007661253).

BP6

Variant 2-108730858-C-G is Benign according to our data. Variant chr2-108730858-C-G is described in ClinVar as [Benign]. Clinvar id is 469439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108730858-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 325 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.225C>G	p.Asn75Lys	missense_variant	3/29	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.225C>G	p.Asn75Lys	missense_variant	3/29	1	NM_006267.5	ENSP00000283195	P1

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

325

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00719

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000663

AC:

166

AN:

250520

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00819

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000269

AC:

393

AN:

1459342

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

725986

show subpopulations

Gnomad4 AFR exome

AF:

0.00785

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000675

Gnomad4 OTH exome

AF:

0.000449

GnomAD4 genome

AF:

0.00213

AC:

325

AN:

152282

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00717

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.00254

ESP6500AA

AF:

0.00644

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000859

AC:

104

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial acute necrotizing encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

- -

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

Uncertain

0.42

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0077

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.16

Sift

Benign

0.21

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.49

MutPred

0.45

Gain of ubiquitination at N75 (P = 0.0117);

MVP

0.73

MPC

0.49

ClinPred

0.038

GERP RS

-0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.4

Varity_R

0.11

gMVP

0.37

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