rs149207118

chr2-108748943-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006267.5(RANBP2):c.1087C>T(p.Arg363Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,800 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R363H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (9 hom., cov: 31)
  • Exomes 𝑓: 0.00061 (9 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.531

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RANBP2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008100748).
• BP6: Variant 2-108748943-C-T is Benign according to our data. Variant chr2-108748943-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 469426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00559 (851/152122) while in subpopulation AFR AF= 0.0196 (813/41496). AF 95% confidence interval is 0.0185. There are 9 homozygotes in gnomad4. There are 411 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 851 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.1087C>T	p.Arg363Cys	missense_variant	9/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.1087C>T	p.Arg363Cys	missense_variant	9/29	1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 851 AN: 152004 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.000118

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00135 AC: 340 AN: 250978 Hom.: 4 AF XY: 0.000936 AC XY: 127 AN XY: 135700

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000610 AC: 891 AN: 1459678 Hom.: 9 Cov.: 32 AF XY: 0.000518 AC XY: 376 AN XY: 726144

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.000872

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: 0.000165

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.00559 AC: 851 AN: 152122 Hom.: 9 Cov.: 31 AF XY: 0.00553 AC XY: 411 AN XY: 74354

Gnomad4 AFR AF: 0.0196

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00159 Hom.: 0

Bravo AF: 0.00597

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00164 AC: 199

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial acute necrotizing encephalopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.55	D;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.080
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.010	B
Vest4		0.41
MVP		0.18
MPC		0.0050
ClinPred		0.032	T
GERP RS		2.8
Varity_R		0.22
gMVP		0.26

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: rs149207118; hg19: chr2-109365399; COSMIC: COSV99032139; COSMIC: COSV99032139;