rs17414315

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006267.5(RANBP2):c.2173A>G(p.Ser725Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,611,980 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S725N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0087 ( 23 hom., cov: 31)

Exomes 𝑓: 0.00085 ( 9 hom. )

Consequence

RANBP2
NM_006267.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.09

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

RANBP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049237907).

BP6

Variant 2-108753942-A-G is Benign according to our data. Variant chr2-108753942-A-G is described in ClinVar as Benign. ClinVar VariationId is 382437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00874 (1331/152336) while in subpopulation AFR AF = 0.0293 (1219/41568). AF 95% confidence interval is 0.028. There are 23 homozygotes in GnomAd4. There are 630 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1331 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5 link	c.2173A>G	p.Ser725Gly	missense_variant	Exon 15 of 29	ENST00000283195.11	NP_006258.3	P49792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RANBP2	ENST00000283195.11 link	c.2173A>G	p.Ser725Gly	missense_variant	Exon 15 of 29	1	NM_006267.5	ENSP00000283195.6	P49792
RANBP2	ENST00000697737.1 link	c.2173A>G	p.Ser725Gly	missense_variant	Exon 15 of 27			ENSP00000513426.1	A0A8V8TL79
RANBP2	ENST00000697740.1 link	c.2095A>G	p.Ser699Gly	missense_variant	Exon 15 of 27			ENSP00000513427.1	A0A8V8TLA0

Frequencies

GnomAD3 genomes

AF:

0.00867

AC:

1319

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00569

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00218

AC:

543

AN:

249538

AF XY:

0.00160

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000974

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000854

AC:

1247

AN:

1459644

Hom.:

Cov.:

AF XY:

0.000756

AC XY:

549

AN XY:

726124

show subpopulations

African (AFR)

AF:

0.0285

AC:

951

AN:

33406

American (AMR)

AF:

0.00192

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.000277

AC:

AN:

39674

South Asian (SAS)

AF:

0.000151

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00169

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000405

AC:

AN:

1111808

Other (OTH)

AF:

0.00223

AC:

134

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00874

AC:

1331

AN:

152336

Hom.:

Cov.:

AF XY:

0.00846

AC XY:

630

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0293

AC:

1219

AN:

41568

American (AMR)

AF:

0.00568

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68040

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

118

177

236

295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00241

Hom.:

Bravo

AF:

0.0102

ESP6500AA

AF:

0.0237

AC:

103

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00265

AC:

321

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial acute necrotizing encephalopathy

Benign:1

Dec 09, 2024

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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0049

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

3.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

REVEL

Benign

0.059

Sift

Benign

0.26

Sift4G

Uncertain

0.046

Polyphen

0.36

Vest4

0.29

MVP

0.45

MPC

0.96

ClinPred

0.019

GERP RS

2.6

Varity_R

0.056

gMVP

0.41

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over