rs2433786

chr2-108767711-C-Gchr2-108767711-C-T

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.7172C>G(p.Thr2391Ser) 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 1,596,446 control chromosomes in the GnomAD database, including 79 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (78 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.22

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=0.021814346).
• BP6: Variant 2-108767711-C-G is Benign according to our data. Variant chr2-108767711-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 469482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108767711-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 782 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.7172C>G	p.Thr2391Ser	missense_variant	20/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.7172C>G	p.Thr2391Ser	missense_variant	20/29	1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 782 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00877

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00117 AC: 292 AN: 248974 Hom.: 2 AF XY: 0.00115 AC XY: 155 AN XY: 135210

Gnomad AFR exome AF: 0.000588

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.00399 AC: 5765 AN: 1444280 Hom.: 78 Cov.: 33 AF XY: 0.00389 AC XY: 2794 AN XY: 718696

Gnomad4 AFR exome AF: 0.000900

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.000996

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000755

Gnomad4 FIN exome AF: 0.00330

Gnomad4 NFE exome AF: 0.00464

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74412

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00321

Gnomad4 NFE AF: 0.00877

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00227 Hom.: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RANBP2: BP4, BS2 -

Familial acute necrotizing encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.042	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.17
Sift	Benign	0.50	T
Sift4G	Benign	0.16	T
Polyphen		0.27	B
Vest4		0.24
MutPred		0.47		Gain of disorder (P = 0.0687);
MVP		0.60
MPC		0.36
ClinPred		0.025	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.056
gMVP		0.10

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: rs2433786; hg19: chr2-109384167; COSMIC: COSV51706519;