rs61758802

Variant names:

• chr2-108755041-C-T
• rs61758802
• NM_006267.5:c.2339C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006267.5(RANBP2):​c.2339C>T​(p.Pro780Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00698 in 1,611,786 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P780P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0072 (84 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.97
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070511103).
• BP6: Variant 2-108755041-C-T is Benign according to our data. Variant chr2-108755041-C-T is described in ClinVar as Benign. ClinVar VariationId is 382461.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 = 0.00503 (765/152148) while in subpopulation SAS AF = 0.0211 (102/4824). AF 95% confidence interval is 0.0178. There are 4 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 765 AD gene.

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.2339C>T	p.Pro780Leu	missense	Exon 16 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.2339C>T	p.Pro780Leu	missense	Exon 16 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.2339C>T	p.Pro780Leu	missense	Exon 16 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.2339C>T	p.Pro780Leu	missense	Exon 16 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.2336C>T	p.Pro779Leu	missense	Exon 16 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2339C>T	p.Pro780Leu	missense	Exon 16 of 28	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 764 AN: 152030 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00551

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00803 AC: 2008 AN: 250080 AF XY: 0.00825

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.0266

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00537

Gnomad OTH exome AF: 0.00806

GnomAD4 exome AF: 0.00718 AC: 10487 AN: 1459638 Hom.: 84 Cov.: 32 AF XY: 0.00750 AC XY: 5449 AN XY: 726132

African (AFR) AF: 0.00105 AC: 35 AN: 33402

American (AMR) AF: 0.00479 AC: 214 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00478 AC: 125 AN: 26128

East Asian (EAS) AF: 0.0346 AC: 1372 AN: 39672

South Asian (SAS) AF: 0.0201 AC: 1732 AN: 86164

European-Finnish (FIN) AF: 0.000711 AC: 38 AN: 53418

Middle Eastern (MID) AF: 0.00532 AC: 22 AN: 4136

European-Non Finnish (NFE) AF: 0.00589 AC: 6554 AN: 1111804

Other (OTH) AF: 0.00656 AC: 395 AN: 60198

GnomAD4 genome AF: 0.00503 AC: 765 AN: 152148 Hom.: 4 Cov.: 30 AF XY: 0.00538 AC XY: 400 AN XY: 74380

African (AFR) AF: 0.00116 AC: 48 AN: 41506

American (AMR) AF: 0.00537 AC: 82 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.0203 AC: 105 AN: 5178

South Asian (SAS) AF: 0.0211 AC: 102 AN: 4824

European-Finnish (FIN) AF: 0.000473 AC: 5 AN: 10578

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00552 AC: 375 AN: 67994

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00565 Hom.: 2

Bravo AF: 0.00504

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00631 AC: 54

ExAC AF: 0.00823 AC: 998

Asia WGS AF: 0.0260 AC: 91 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Familial acute necrotizing encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.088
Eigen_PC	Benign	0.074
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Benign	0.11
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.080	B
Vest4		0.23
MVP		0.30
MPC		1.1
ClinPred		0.039	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.53
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs61758802; hg19: chr2-109371497; COSMIC: COSV51696907; COSMIC: COSV51696907;