2-108768038-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.7499C>T(p.Thr2500Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,612,012 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (19 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:8
• Conservation: PhyloP100: 1.61

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=0.0037479103).
• BP6: Variant 2-108768038-C-T is Benign according to our data. Variant chr2-108768038-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 380569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108768038-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 200 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.7499C>T	p.Thr2500Ile	missense_variant	20/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.7499C>T	p.Thr2500Ile	missense_variant	20/29	1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152192 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00281 AC: 705 AN: 251110 Hom.: 5 AF XY: 0.00310 AC XY: 421 AN XY: 135714

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00735

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00163 AC: 2376 AN: 1459702 Hom.: 19 Cov.: 33 AF XY: 0.00187 AC XY: 1357 AN XY: 726158

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.0272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00722

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000698

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152310 Hom.: 7 Cov.: 31 AF XY: 0.00140 AC XY: 104 AN XY: 74480

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00706

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00369 Hom.: 1

Bravo AF: 0.00128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00272 AC: 330

EpiCase AF: 0.00202

EpiControl AF: 0.00207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	RANBP2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial acute necrotizing encephalopathy Pathogenic:1 Benign:2

Likely pathogenic, no assertion criteria provided	clinical testing	Kamineni Academy of Medical Sciences & Research Centre, Kamineni Hospitals	Oct 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.067
Sift	Benign	0.040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.055	B
Vest4		0.16
MVP		0.27
MPC		0.45
ClinPred		0.038	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.29

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: rs140280672; hg19: chr2-109384494; COSMIC: COSV51708640;