rs764830622
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_006267.5(RANBP2):c.3860C>T(p.Thr1287Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
RANBP2
NM_006267.5 missense
NM_006267.5 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 7.90
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, RANBP2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.815
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RANBP2 | NM_006267.5 | c.3860C>T | p.Thr1287Ile | missense_variant | 20/29 | ENST00000283195.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RANBP2 | ENST00000283195.11 | c.3860C>T | p.Thr1287Ile | missense_variant | 20/29 | 1 | NM_006267.5 | P1 | |
RANBP2 | ENST00000697737.1 | c.2602+5851C>T | intron_variant | ||||||
RANBP2 | ENST00000697740.1 | c.2524+5851C>T | intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250240Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135622
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461750Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727186
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial acute necrotizing encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1287 of the RANBP2 protein (p.Thr1287Ile). This variant is present in population databases (rs764830622, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RANBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 537210). 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. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of phosphorylation at T1287 (P = 0.0087);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at