chr2-108729132-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS2_Supporting

The NM_006267.5(RANBP2):​c.73A>G​(p.Lys25Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,569,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

RANBP2
NM_006267.5 missense, splice_region

Scores

1
11
7
Splicing: ADA: 0.4006
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.20
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 Likely_benign. Variant got -2 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RANBP2. . Gene score misZ -0.77637 (greater than the threshold 3.09). Trascript score misZ 3.8106 (greater than threshold 3.09). GenCC has associacion of gene with Leigh syndrome, familial acute necrotizing encephalopathy.
BP4
Computational evidence support a benign effect (MetaRNN=0.22755244).
BS2
High AC in GnomAd4 at 16 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RANBP2NM_006267.5 linkuse as main transcriptc.73A>G p.Lys25Glu missense_variant, splice_region_variant 2/29 ENST00000283195.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RANBP2ENST00000283195.11 linkuse as main transcriptc.73A>G p.Lys25Glu missense_variant, splice_region_variant 2/291 NM_006267.5 P1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000436
AC:
10
AN:
229504
Hom.:
0
AF XY:
0.0000240
AC XY:
3
AN XY:
125248
show subpopulations
Gnomad AFR exome
AF:
0.000360
Gnomad AMR exome
AF:
0.000120
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:
0.00000918
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000106
AC:
15
AN:
1417598
Hom.:
0
Cov.:
31
AF XY:
0.00000709
AC XY:
5
AN XY:
705180
show subpopulations
Gnomad4 AFR exome
AF:
0.000214
Gnomad4 AMR exome
AF:
0.000115
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:
0.00000183
Gnomad4 OTH exome
AF:
0.0000170
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.000185
ExAC
AF:
0.0000421
AC:
5

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 17, 2023This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 25 of the RANBP2 protein (p.Lys25Glu). This variant is present in population databases (rs576251747, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 650442). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.60
D;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.046
D
MetaRNN
Benign
0.23
T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Uncertain
2.0
M;.
MutationTaster
Benign
0.77
D;N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-2.5
D;.
REVEL
Benign
0.18
Sift
Uncertain
0.0080
D;.
Sift4G
Uncertain
0.0030
D;T
Polyphen
0.96
P;.
Vest4
0.64
MutPred
0.28
Loss of methylation at K25 (P = 0.0011);Loss of methylation at K25 (P = 0.0011);
MVP
0.40
MPC
0.64
ClinPred
0.14
T
GERP RS
4.3
Varity_R
0.40
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.40
dbscSNV1_RF
Benign
0.58
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: rs576251747; hg19: chr2-109345588; API