2-108719608-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_006267.5(RANBP2):​c.2T>A​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RANBP2
NM_006267.5 start_lost

Scores

5
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36
Variant links:
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 3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 78 CDS bases. Genomic position: 108729137. Lost 0.008 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RANBP2NM_006267.5 linkc.2T>A p.Met1? start_lost Exon 1 of 29 ENST00000283195.11 NP_006258.3 P49792

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RANBP2ENST00000283195.11 linkc.2T>A p.Met1? start_lost Exon 1 of 29 1 NM_006267.5 ENSP00000283195.6 P49792
RANBP2ENST00000697737.1 linkc.2T>A p.Met1? start_lost Exon 1 of 27 ENSP00000513426.1 A0A8V8TL79
RANBP2ENST00000425282.4 linkn.2T>A non_coding_transcript_exon_variant Exon 1 of 4 5 ENSP00000398970.2 F8WBP7
RANBP2ENST00000697738.1 linkn.111T>A non_coding_transcript_exon_variant Exon 1 of 10

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial acute necrotizing encephalopathy Uncertain:1
May 20, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. ClinVar contains an entry for this variant (Variation ID: 1025191). This variant has not been reported in the literature in individuals affected with RANBP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the RANBP2 mRNA. The next in-frame methionine is located at codon 27. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Uncertain
0.75
D;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Benign
0.57
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Benign
-0.98
T
PROVEAN
Pathogenic
-4.5
D;.
REVEL
Uncertain
0.44
Sift
Uncertain
0.0010
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.93
P;.
Vest4
0.90
MutPred
0.99
Loss of stability (P = 0.0056);Loss of stability (P = 0.0056);
MVP
0.79
ClinPred
0.98
D
GERP RS
4.5
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.7
Varity_R
0.95
gMVP
0.83

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1694042679; hg19: chr2-109336064; API