rs769995347

chr2-108749108-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_006267.5(RANBP2):c.1252G>T(p.Asp418Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,611,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RANBP2
• BS2: High AC in GnomAdExome at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.1252G>T	p.Asp418Tyr	missense_variant	9/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.1252G>T	p.Asp418Tyr	missense_variant	9/29	1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 251104 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1459680 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 726148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial acute necrotizing encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2022

ClinVar contains an entry for this variant (Variation ID: 570364). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with RANBP2-related conditions. This variant is present in population databases (rs769995347, gnomAD 0.009%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 418 of the RANBP2 protein (p.Asp418Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.94	D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.67
MutPred		0.34		Loss of disorder (P = 0.0319);
MVP		0.58
MPC		0.0077
ClinPred		0.50	T
GERP RS		5.4
Varity_R		0.52
gMVP		0.49

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: rs769995347; hg19: chr2-109365564;