rs13426055

Positions:

• chr2-108758508-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006267.5(RANBP2):​c.2562A>G​(p.Gly854Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,610,956 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (142 hom., cov: 27)
  • Exomes 𝑓: 0.0024 (160 hom.)
• Consequence: RANBP2 NM_006267.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.77

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-108758508-A-G is Benign according to our data. Variant chr2-108758508-A-G is described in ClinVar as [Benign]. Clinvar id is 382089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.2562A>G	p.Gly854Gly	synonymous_variant	18/29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.2562A>G	p.Gly854Gly	synonymous_variant	18/29	1	NM_006267.5	ENSP00000283195.6
RANBP2	ENST00000697737.1	c.2562A>G	p.Gly854Gly	synonymous_variant	18/27			ENSP00000513426.1
RANBP2	ENST00000697740.1	c.2484A>G	p.Gly828Gly	synonymous_variant	18/27			ENSP00000513427.1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3583 AN: 151314 Hom.: 140 Cov.: 27

Gnomad AFR AF: 0.0831

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00921

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000420

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0159

GnomAD3 exomes AF: 0.00633 AC: 1589 AN: 250882 Hom.: 71 AF XY: 0.00452 AC XY: 613 AN XY: 135694

Gnomad AFR exome AF: 0.0850

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00244 AC: 3560 AN: 1459528 Hom.: 160 Cov.: 35 AF XY: 0.00209 AC XY: 1519 AN XY: 726092

Gnomad4 AFR exome AF: 0.0870

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.00542

GnomAD4 genome AF: 0.0238 AC: 3604 AN: 151428 Hom.: 142 Cov.: 27 AF XY: 0.0231 AC XY: 1707 AN XY: 74014

Gnomad4 AFR AF: 0.0834

Gnomad4 AMR AF: 0.00920

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0157

Alfa AF: 0.0138 Hom.: 14

Bravo AF: 0.0273

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 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

Jan 23, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.50
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: rs13426055; hg19: chr2-109374964;