2-108768392-A-G

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.7849+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00469 in 1,599,878 control chromosomes in the GnomAD database, including 116 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 111 hom. )

Consequence

RANBP2
NM_006267.5 splice_region, intron

Scores

Splicing: ADA: 0.03582

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.98

Publications

4 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 (BayesDel_noAF=-0.49).

BP6

Variant 2-108768392-A-G is Benign according to our data. Variant chr2-108768392-A-G is described in ClinVar as Benign. ClinVar VariationId is 382464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00582 (886/152106) while in subpopulation SAS AF = 0.0211 (102/4832). AF 95% confidence interval is 0.0178. There are 5 homozygotes in GnomAd4. There are 450 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 886 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5 link	c.7849+4A>G		splice_region_variant, intron_variant	Intron 20 of 28	ENST00000283195.11	NP_006258.3	P49792

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11 link	c.7849+4A>G		splice_region_variant, intron_variant	Intron 20 of 28	1	NM_006267.5	ENSP00000283195.6		P49792

Frequencies

GnomAD3 genomes

AF:

0.00582

AC:

885

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.00837

Gnomad EAS

AF:

0.0202

Gnomad SAS

AF:

0.0209

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00685

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00479

AC:

1169

AN:

243906

AF XY:

0.00465

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00259

Gnomad ASJ exome

AF:

0.00345

Gnomad EAS exome

AF:

0.0159

Gnomad FIN exome

AF:

0.000238

Gnomad NFE exome

AF:

0.00353

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.00457

AC:

6620

AN:

1447772

Hom.:

111

Cov.:

AF XY:

0.00488

AC XY:

3512

AN XY:

720314

show subpopulations

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

African (AFR)

AF:

0.000719

AC:

AN:

33368

American (AMR)

AF:

0.00267

AC:

119

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.00516

AC:

134

AN:

25972

East Asian (EAS)

AF:

0.0301

AC:

1181

AN:

39300

South Asian (SAS)

AF:

0.0144

AC:

1227

AN:

85188

European-Finnish (FIN)

AF:

0.000648

AC:

AN:

52466

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.00327

AC:

3611

AN:

1103038

Other (OTH)

AF:

0.00463

AC:

277

AN:

59828

⚠️ 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: 0.380

Heterozygous variant carriers

367

734

1102

1469

1836

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00582

AC:

886

AN:

152106

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

450

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41560

American (AMR)

AF:

0.00595

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00837

AC:

AN:

3466

East Asian (EAS)

AF:

0.0202

AC:

105

AN:

5186

South Asian (SAS)

AF:

0.0211

AC:

102

AN:

4832

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00686

AC:

465

AN:

67828

Other (OTH)

AF:

0.0119

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

105

140

175

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:

0.00661

Hom.:

Bravo

AF:

0.00662

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

4.0

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.036

dbscSNV1_RF

Benign

0.41

SpliceAI score (max)

0.010

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