rs61758804

chr2-108775846-A-G

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.8407A>G(p.Ile2803Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,613,754 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (25 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.99

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=0.0039082468).
• BP6: Variant 2-108775846-A-G is Benign according to our data. Variant chr2-108775846-A-G is described in ClinVar as [Benign]. Clinvar id is 377298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108775846-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 413 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.8407A>G	p.Ile2803Val	missense_variant	24/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.8407A>G	p.Ile2803Val	missense_variant	24/29	1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00269 AC: 675 AN: 251124 Hom.: 6 AF XY: 0.00262 AC XY: 355 AN XY: 135730

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00437

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00425 AC: 6211 AN: 1461434 Hom.: 25 Cov.: 31 AF XY: 0.00403 AC XY: 2930 AN XY: 727034

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000985

Gnomad4 FIN exome AF: 0.00498

Gnomad4 NFE exome AF: 0.00496

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00252 AC XY: 188 AN XY: 74490

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00416

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00373 Hom.: 2

Bravo AF: 0.00261

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00315 AC: 382

Asia WGS AF: 0.000867 AC: 4 AN: 3474

EpiCase AF: 0.00371

EpiControl AF: 0.00344

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 04, 2017	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	RANBP2: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 30, 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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.0030
Dann	Benign	0.41
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.035
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.080
MVP		0.21
MPC		0.29
ClinPred		0.00070	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.013
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs61758804; hg19: chr2-109392302;