rs13426055

Variant names:

• chr2-108758508-A-G
• rs13426055
• NM_006267.5:c.2562A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	NM_006267.5	MANE Select	c.2562A>G	p.Gly854Gly	synonymous	Exon 18 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.2562A>G	p.Gly854Gly	synonymous	Exon 18 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.2562A>G	p.Gly854Gly	synonymous	Exon 18 of 29	NP_001402802.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.2562A>G	p.Gly854Gly	synonymous	Exon 18 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.2559A>G	p.Gly853Gly	synonymous	Exon 18 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2562A>G	p.Gly854Gly	synonymous	Exon 18 of 28	ENSP00000630145.1

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

GnomAD2 exomes AF: 0.00633 AC: 1589 AN: 250882 AF XY: 0.00452

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 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

African (AFR) AF: 0.0870 AC: 2895 AN: 33274

American (AMR) AF: 0.00550 AC: 246 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00242 AC: 10 AN: 4134

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111832

Other (OTH) AF: 0.00542 AC: 326 AN: 60166

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

African (AFR) AF: 0.0834 AC: 3422 AN: 41030

American (AMR) AF: 0.00920 AC: 140 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67922

Other (OTH) AF: 0.0157 AC: 33 AN: 2100

Alfa AF: 0.0138 Hom.: 14

Bravo AF: 0.0273

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial acute necrotizing encephalopathy (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.50
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13426055; hg19: chr2-109374964;