rs377422691
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_006267.5(RANBP2):c.7066G>A(p.Asp2356Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000323 in 1,611,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
RANBP2
NM_006267.5 missense
NM_006267.5 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 6.92
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 Likely_benign. Variant got -4 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, RANBP2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.33857685).
BS2
?
High AC in GnomAd4 at 29 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RANBP2 | NM_006267.5 | c.7066G>A | p.Asp2356Asn | missense_variant | 20/29 | ENST00000283195.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RANBP2 | ENST00000283195.11 | c.7066G>A | p.Asp2356Asn | missense_variant | 20/29 | 1 | NM_006267.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000191 AC: 29AN: 152126Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000363 AC: 9AN: 247960Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134906
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GnomAD4 exome AF: 0.0000158 AC: 23AN: 1459696Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 726154
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GnomAD4 genome ? AF: 0.000191 AC: 29AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74310
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2023 | The c.7066G>A (p.D2356N) alteration is located in exon 20 (coding exon 20) of the RANBP2 gene. This alteration results from a G to A substitution at nucleotide position 7066, causing the aspartic acid (D) at amino acid position 2356 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Familial acute necrotizing encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 469481). This variant has not been reported in the literature in individuals affected with RANBP2-related conditions. This variant is present in population databases (rs377422691, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 2356 of the RANBP2 protein (p.Asp2356Asn). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
T
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
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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