chr2-108763521-A-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_006267.5(RANBP2):​c.2982A>T​(p.Ala994Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00607 in 1,614,172 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 5 hom., cov: 31)
Exomes 𝑓: 0.0062 ( 43 hom. )

Consequence

RANBP2
NM_006267.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.321

Publications

2 publications found
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]
RANBP2 Gene-Disease associations (from GenCC):
  • familial acute necrotizing encephalopathy
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • Leigh syndrome
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 2-108763521-A-T is Benign according to our data. Variant chr2-108763521-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.321 with no splicing effect.
BS2
High AC in GnomAd4 at 726 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RANBP2NM_006267.5 linkc.2982A>T p.Ala994Ala synonymous_variant Exon 20 of 29 ENST00000283195.11 NP_006258.3 P49792

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RANBP2ENST00000283195.11 linkc.2982A>T p.Ala994Ala synonymous_variant Exon 20 of 29 1 NM_006267.5 ENSP00000283195.6 P49792
RANBP2ENST00000697737.1 linkc.2602+4973A>T intron_variant Intron 18 of 26 ENSP00000513426.1 A0A8V8TL79
RANBP2ENST00000697740.1 linkc.2524+4973A>T intron_variant Intron 18 of 26 ENSP00000513427.1 A0A8V8TLA0

Frequencies

GnomAD3 genomes
AF:
0.00477
AC:
726
AN:
152218
Hom.:
5
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00138
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.0102
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00122
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00694
Gnomad OTH
AF:
0.00813
GnomAD2 exomes
AF:
0.00453
AC:
1137
AN:
251130
AF XY:
0.00452
show subpopulations
Gnomad AFR exome
AF:
0.00117
Gnomad AMR exome
AF:
0.00720
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00139
Gnomad NFE exome
AF:
0.00684
Gnomad OTH exome
AF:
0.00669
GnomAD4 exome
AF:
0.00621
AC:
9078
AN:
1461836
Hom.:
43
Cov.:
34
AF XY:
0.00608
AC XY:
4423
AN XY:
727228
show subpopulations
African (AFR)
AF:
0.000896
AC:
30
AN:
33476
American (AMR)
AF:
0.00713
AC:
319
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.000918
AC:
24
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.000556
AC:
48
AN:
86258
European-Finnish (FIN)
AF:
0.00118
AC:
63
AN:
53414
Middle Eastern (MID)
AF:
0.00641
AC:
37
AN:
5768
European-Non Finnish (NFE)
AF:
0.00740
AC:
8224
AN:
1111976
Other (OTH)
AF:
0.00551
AC:
333
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
661
1322
1984
2645
3306
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
302
604
906
1208
1510
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00477
AC:
726
AN:
152336
Hom.:
5
Cov.:
31
AF XY:
0.00477
AC XY:
355
AN XY:
74498
show subpopulations
African (AFR)
AF:
0.00137
AC:
57
AN:
41574
American (AMR)
AF:
0.0102
AC:
156
AN:
15310
Ashkenazi Jewish (ASJ)
AF:
0.000576
AC:
2
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5188
South Asian (SAS)
AF:
0.00104
AC:
5
AN:
4828
European-Finnish (FIN)
AF:
0.00122
AC:
13
AN:
10616
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.00694
AC:
472
AN:
68030
Other (OTH)
AF:
0.00804
AC:
17
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
32
65
97
130
162
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00535
Hom.:
1
Bravo
AF:
0.00543
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00720
EpiControl
AF:
0.00818

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

RANBP2: BP4, BP7, BS2 -

not specified Benign:1
Apr 22, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial acute necrotizing encephalopathy Benign:1
Jan 15, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
CADD
Benign
6.5
DANN
Benign
0.63
PhyloP100
0.32
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs61748148; hg19: chr2-109379977; API