2-108764000-A-T

Position:

chr2-108764000-A-T

Variant summary

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

The ENST00000283195.11(RANBP2):c.3461A>T(p.His1154Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,613,944 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 4 hom. )

Consequence

RANBP2
ENST00000283195.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.09

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=0.0069001317).

BP6

Variant 2-108764000-A-T is Benign according to our data. Variant chr2-108764000-A-T is described in ClinVar as [Benign]. Clinvar id is 469453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108764000-A-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 385 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.3461A>T	p.His1154Leu	missense_variant	20/29	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.3461A>T	p.His1154Leu	missense_variant	20/29	1	NM_006267.5	ENSP00000283195	P1
RANBP2	ENST00000697737.1 linkuse as main transcript	c.2602+5452A>T		intron_variant				ENSP00000513426
RANBP2	ENST00000697740.1 linkuse as main transcript	c.2524+5452A>T		intron_variant				ENSP00000513427

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

383

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00883

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000685

AC:

172

AN:

251048

Hom.:

AF XY:

0.000590

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00991

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000216

AC:

315

AN:

1461662

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

135

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00735

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.00253

AC:

385

AN:

152282

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00885

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.0000908

Hom.:

Bravo

AF:

0.00290

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000865

AC:

105

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

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

0.079

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.27

DEOGEN2

Uncertain

0.72

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0069

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.7

REVEL

Benign

0.061

Sift

Benign

0.34

Sift4G

Benign

0.23

Polyphen

0.15

Vest4

0.29

MVP

0.49

MPC

0.45

ClinPred

0.032

GERP RS

3.1

Varity_R

0.16

gMVP

0.32

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