chr2-108763902-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006267.5(RANBP2):c.3363G>T(p.Lys1121Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,613,914 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00035 ( 2 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.02

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

familial acute necrotizing encephalopathy
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065559745).

BP6

Variant 2-108763902-G-T is Benign according to our data. Variant chr2-108763902-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469452.

BS2

High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5 link	c.3363G>T	p.Lys1121Asn	missense_variant	Exon 20 of 29	ENST00000283195.11	NP_006258.3	P49792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RANBP2	ENST00000283195.11 link	c.3363G>T	p.Lys1121Asn	missense_variant	Exon 20 of 29	1	NM_006267.5	ENSP00000283195.6	P49792
RANBP2	ENST00000697737.1 link	c.2602+5354G>T		intron_variant	Intron 18 of 26			ENSP00000513426.1	A0A8V8TL79
RANBP2	ENST00000697740.1 link	c.2524+5354G>T		intron_variant	Intron 18 of 26			ENSP00000513427.1	A0A8V8TLA0

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000576

AC:

144

AN:

249792

AF XY:

0.000458

show subpopulations

Gnomad AFR exome

AF:

0.000509

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00597

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000231

Gnomad OTH exome

AF:

0.000986

GnomAD4 exome

AF:

0.000347

AC:

507

AN:

1461660

Hom.:

Cov.:

AF XY:

0.000331

AC XY:

241

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

33472

American (AMR)

AF:

0.00123

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00536

AC:

140

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000156

AC:

173

AN:

1111964

Other (OTH)

AF:

0.00104

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000598

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41560

American (AMR)

AF:

0.000196

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68006

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000537

Hom.:

Bravo

AF:

0.000631

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000469

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RANBP2: BP4, BS1 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial acute necrotizing encephalopathy

Uncertain:1Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2020

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.59

M_CAP

Benign

0.0068

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

2.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.2

REVEL

Benign

0.036

Sift

Benign

0.066

Sift4G

Uncertain

0.0050

Polyphen

0.26

Vest4

0.45

MutPred

0.12

Loss of ubiquitination at K1121 (P = 0.0012);

MVP

0.50

MPC

0.41

ClinPred

0.0093

GERP RS

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.36

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over