rs145886643

chr2-108768293-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_006267.5(RANBP2):c.7754T>C(p.Ile2585Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,612,030 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I2585I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (42 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.59

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RANBP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031910837).
• BP6: Variant 2-108768293-T-C is Benign according to our data. Variant chr2-108768293-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 380577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108768293-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 728 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.7754T>C	p.Ile2585Thr	missense_variant	20/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.7754T>C	p.Ile2585Thr	missense_variant	20/29	1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 728 AN: 152222 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00453 AC: 1128 AN: 248980 Hom.: 6 AF XY: 0.00454 AC XY: 614 AN XY: 135270

Gnomad AFR exome AF: 0.000992

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.00622 AC: 9080 AN: 1459690 Hom.: 42 Cov.: 33 AF XY: 0.00609 AC XY: 4423 AN XY: 726150

Gnomad4 AFR exome AF: 0.000898

Gnomad4 AMR exome AF: 0.00718

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000557

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.00740

Gnomad4 OTH exome AF: 0.00550

GnomAD4 genome AF: 0.00478 AC: 728 AN: 152340 Hom.: 5 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74494

Gnomad4 AFR AF: 0.00139

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00695

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00477 Hom.: 1

Bravo AF: 0.00544

ESP6500AA AF: 0.00183 AC: 8

ESP6500EA AF: 0.00643 AC: 55

ExAC AF: 0.00443 AC: 537

EpiCase AF: 0.00720

EpiControl AF: 0.00824

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RANBP2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 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

Invitae

Dec 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.0020
Dann	Benign	0.22
DEOGEN2	Benign	0.14	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.054
Sift	Benign	0.68	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.039
MVP		0.14
MPC		0.44
ClinPred		0.00074	T
GERP RS		-10
Varity_R		0.015
gMVP		0.14

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

Other links and lift over

dbSNP: rs145886643; hg19: chr2-109384749;