rs61748148

Positions:

• chr2-108763521-A-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006267.5(RANBP2):​c.2982A>T​(p.Ala994=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00607 in 1,614,172 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (43 hom.)
• Consequence: RANBP2 NM_006267.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.321

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-108763521-A-T is Benign according to our data. Variant chr2-108763521-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 380576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763521-A-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.321 with no splicing effect.
• BS2: High AC in GnomAd4 at 726 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.2982A>T	p.Ala994=	synonymous_variant	20/29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.2982A>T	p.Ala994=	synonymous_variant	20/29	1	NM_006267.5	ENSP00000283195	P1
RANBP2	ENST00000697737.1	c.2602+4973A>T		intron_variant				ENSP00000513426
RANBP2	ENST00000697740.1	c.2524+4973A>T		intron_variant				ENSP00000513427

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 726 AN: 152218 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00694

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00453 AC: 1137 AN: 251130 Hom.: 6 AF XY: 0.00452 AC XY: 614 AN XY: 135722

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00720

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00684

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00621 AC: 9078 AN: 1461836 Hom.: 43 Cov.: 34 AF XY: 0.00608 AC XY: 4423 AN XY: 727228

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00713

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000556

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.00740

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.00477 AC: 726 AN: 152336 Hom.: 5 Cov.: 31 AF XY: 0.00477 AC XY: 355 AN XY: 74498

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00694

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00535 Hom.: 1

Bravo AF: 0.00543

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RANBP2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2016

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.5
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs61748148; hg19: chr2-109379977;