rs121434502

Positions:

chr2-108751993-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP2PP5_Very_StrongBP4

The NM_006267.5(RANBP2):c.1754C>T(p.Thr585Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RANBP2
NM_006267.5 missense, splice_region

Scores

Splicing: ADA: 0.03690

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:2

Conservation

PhyloP100: 2.85

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP5

Variant 2-108751993-C-T is Pathogenic according to our data. Variant chr2-108751993-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108751993-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.23123261). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5 linkuse as main transcript	c.1754C>T	p.Thr585Met	missense_variant, splice_region_variant	12/29	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.1754C>T	p.Thr585Met	missense_variant, splice_region_variant	12/29	1	NM_006267.5	ENSP00000283195	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000478

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459664

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.000478

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial acute necrotizing encephalopathy

Pathogenic:7Other:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic carriers are well-reported in the literature (PMID: 19118815, 30796099). Penetrance was estimated at 40% in one large family (PMID: 19118815). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The p.(Thr585Met) variant is recurrent in individuals with acute infection-induced encephalopathy, and has been reported de novo and in families with incomplete penetrance (ClinVar, PMID: 19118815, 30796099, 27591117). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
risk factor, no assertion criteria provided	literature only	OMIM	Jan 04, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jun 24, 2023	This variant has been identified in a proband with acute necrotizing encephalopathy. The phenotype observed in the proband was encephalopathy and seizures after febrile illness. This variant has also been segregated in the mother. This variant is not found in gnomAD (PM2_moderate). This variant has been previously reported PMID: 32760653 (PP5_very strong). PMID 19811512 has reported the presence of a heterozygous c.1880C>T in mother as well as the proband and the encephalopathy was triggered post a viral infection or illness. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Oct 29, 2024	A 5.5-year-old girl patient and her father were heterozygote for the variant NM_006267.5:c.1754C>T. The patient's father had no clinical symptoms related to RANBP2. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 585 of the RANBP2 protein (p.Thr585Met). This variant is present in population databases (rs121434502, gnomAD no frequency). This missense change has been observed in individual(s) with acute necrotizing encephalopathy (ANE) (PMID: 19118815, 19811512, 20473521, 21205700, 21945312, 25128471, 25522933, 26110162, 26923722, 27591117, 28336122). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8363). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21205700, 20473521, 29741717, 34377735, 33879512, 24321870, 25128471, 26923722, 27591117, 19811512, 21945312, 28336122, 25522933, 30796099, 29687329, 31589614, 33726816, 32760653, 34059398, 19118815, 34400285, 33777149, 33761695) -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Feb 28, 2023

ACMG categories: PS4,PM2,PP5,BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.0016

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Benign

-0.11

Eigen_PC

Benign

0.020

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.73

M_CAP

Benign

0.0090

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

REVEL

Benign

0.18

Sift

Benign

0.13

Sift4G

Benign

0.45

Polyphen

0.17

Vest4

0.32

MutPred

0.73

Gain of helix (P = 0.0425);

MVP

0.88

MPC

1.3

ClinPred

0.33

GERP RS

3.9

Varity_R

0.023

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.037

dbscSNV1_RF

Benign

0.11

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