rs61748147

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006267.5(RANBP2):c.2955G>A(p.Pro985Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,614,010 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 31)

Exomes 𝑓: 0.0072 ( 88 hom. )

Consequence

RANBP2
NM_006267.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.290

Publications

5 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 2-108763494-G-A is Benign according to our data. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in CliVar as Benign. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00501 (763/152188) while in subpopulation SAS AF = 0.0212 (102/4814). AF 95% confidence interval is 0.0179. There are 4 homozygotes in GnomAd4. There are 398 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 763 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5 link	c.2955G>A	p.Pro985Pro	synonymous_variant	Exon 20 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.2955G>A	p.Pro985Pro	synonymous_variant	Exon 20 of 29	1	NM_006267.5	ENSP00000283195.6	P49792
RANBP2	ENST00000697737.1 link	c.2602+4946G>A		intron_variant	Intron 18 of 26			ENSP00000513426.1	A0A8V8TL79
RANBP2	ENST00000697740.1 link	c.2524+4946G>A		intron_variant	Intron 18 of 26			ENSP00000513427.1	A0A8V8TLA0

Frequencies

GnomAD3 genomes

AF:

0.00501

AC:

762

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00635

Gnomad EAS

AF:

0.0200

Gnomad SAS

AF:

0.0210

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00547

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00801

AC:

2010

AN:

251066

AF XY:

0.00828

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00466

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.0266

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00537

Gnomad OTH exome

AF:

0.00801

GnomAD4 exome

AF:

0.00718

AC:

10493

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00750

AC XY:

5457

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33476

American (AMR)

AF:

0.00479

AC:

214

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00482

AC:

126

AN:

26134

East Asian (EAS)

AF:

0.0346

AC:

1373

AN:

39698

South Asian (SAS)

AF:

0.0201

AC:

1734

AN:

86256

European-Finnish (FIN)

AF:

0.000711

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00589

AC:

6549

AN:

1111968

Other (OTH)

AF:

0.00656

AC:

396

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

800

1600

2399

3199

3999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.00501

AC:

763

AN:

152188

Hom.:

Cov.:

AF XY:

0.00535

AC XY:

398

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41526

American (AMR)

AF:

0.00536

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

AN:

3466

East Asian (EAS)

AF:

0.0201

AC:

104

AN:

5186

South Asian (SAS)

AF:

0.0212

AC:

102

AN:

4814

European-Finnish (FIN)

AF:

0.000472

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00547

AC:

372

AN:

68000

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

146

182

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:

0.00505

Hom.:

Bravo

AF:

0.00504

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 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

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.9

(source)

DANN

Benign

0.36

PhyloP100

0.29

Mutation Taster

=100/0

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

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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