dbSNP rs826549: RANBP2:p.Ser850Ser (chr2-108758496-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006267.5(RANBP2):c.2550A>G(p.Ser850Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 150,522 control chromosomes in the GnomAD database, including 12,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 12730 hom., cov: 27)

Exomes 𝑓: 0.25 ( 49902 hom. )

Failed GnomAD Quality Control

Consequence

RANBP2
NM_006267.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.202

Publications

9 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, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
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=-0.83).

BP6

Variant 2-108758496-A-G is Benign according to our data. Variant chr2-108758496-A-G is described in ClinVar as Benign. ClinVar VariationId is 380029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.202 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006267.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RANBP2	NM_006267.5	MANE Select	c.2550A>G	p.Ser850Ser	synonymous	Exon 18 of 29	NP_006258.3
RANBP2	NM_001415871.1		c.2550A>G	p.Ser850Ser	synonymous	Exon 18 of 30	NP_001402800.1
RANBP2	NM_001415873.1		c.2550A>G	p.Ser850Ser	synonymous	Exon 18 of 29	NP_001402802.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.2550A>G	p.Ser850Ser	synonymous	Exon 18 of 29	ENSP00000283195.6	P49792
RANBP2	ENST00000917983.1		c.2547A>G	p.Ser849Ser	synonymous	Exon 18 of 29	ENSP00000588042.1
RANBP2	ENST00000960086.1		c.2550A>G	p.Ser850Ser	synonymous	Exon 18 of 28	ENSP00000630145.1

Frequencies

GnomAD3 genomes

AF:

0.353

AC:

53075

AN:

150404

Hom.:

12680

Cov.:

show subpopulations

Gnomad AFR

AF:

0.685

Gnomad AMI

AF:

0.269

Gnomad AMR

AF:

0.246

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.0700

Gnomad SAS

AF:

0.336

Gnomad FIN

AF:

0.180

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.312

GnomAD2 exomes

AF:

0.246

AC:

61490

AN:

249652

AF XY:

0.246

show subpopulations

Gnomad AFR exome

AF:

0.699

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.236

Gnomad EAS exome

AF:

0.0455

Gnomad FIN exome

AF:

0.190

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.244

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.248

AC:

360529

AN:

1456270

Hom.:

49902

Cov.:

AF XY:

0.249

AC XY:

180793

AN XY:

724664

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.708

AC:

23520

AN:

33228

American (AMR)

AF:

0.163

AC:

7279

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

6414

AN:

26110

East Asian (EAS)

AF:

0.0969

AC:

3845

AN:

39692

South Asian (SAS)

AF:

0.329

AC:

28286

AN:

86048

European-Finnish (FIN)

AF:

0.192

AC:

10232

AN:

53416

Middle Eastern (MID)

AF:

0.288

AC:

1188

AN:

4128

European-Non Finnish (NFE)

AF:

0.238

AC:

263736

AN:

1108874

Other (OTH)

AF:

0.267

AC:

16029

AN:

60072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.369

Heterozygous variant carriers

14749

29497

44246

58994

73743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9088

18176

27264

36352

45440

<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:

0.353

AC:

53188

AN:

150522

Hom.:

12730

Cov.:

AF XY:

0.347

AC XY:

25551

AN XY:

73562

show subpopulations

African (AFR)

AF:

0.686

AC:

27835

AN:

40586

American (AMR)

AF:

0.245

AC:

3707

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

853

AN:

3460

East Asian (EAS)

AF:

0.0698

AC:

360

AN:

5160

South Asian (SAS)

AF:

0.335

AC:

1582

AN:

4722

European-Finnish (FIN)

AF:

0.180

AC:

1885

AN:

10474

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.236

AC:

15973

AN:

67714

Other (OTH)

AF:

0.319

AC:

664

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

1230

2459

3689

4918

6148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<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:

0.294

Hom.:

1514

Bravo

AF:

0.372

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial acute necrotizing encephalopathy (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.4

(source)

DANN

Benign

0.64

PhyloP100

-0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over