rs183569993

chr2-108771695-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The NM_006267.5(RANBP2):c.7850-6T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,611,682 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: RANBP2 NM_006267.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9852
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-108771695-T-G is Benign according to our data. Variant chr2-108771695-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 469490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108771695-T-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 413 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.7850-6T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.7850-6T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00283 AC: 704 AN: 248354 Hom.: 3 AF XY: 0.00302 AC XY: 406 AN XY: 134598

Gnomad AFR exome AF: 0.000567

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.00613

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00343 AC: 5000 AN: 1459394 Hom.: 12 Cov.: 31 AF XY: 0.00346 AC XY: 2514 AN XY: 726090

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.00556

Gnomad4 NFE exome AF: 0.00372

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74474

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.00401

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00387 Hom.: 1

Bravo AF: 0.00176

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial acute necrotizing encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

RANBP2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	16
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.76
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

LitVar

Other links and lift over

dbSNP: rs183569993; hg19: chr2-109388151;