rs148999619

Variant names:

• chr2-108758505-T-A
• rs148999619
• NM_006267.5:c.2559T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-108758505-T-A
• chr2-108758505-T-C

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.2559T>A​(p.Asp853Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,611,274 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (48 hom., cov: 27)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.531
• Publications: 1 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=0.0040726364).
• BP6: Variant 2-108758505-T-A is Benign according to our data. Variant chr2-108758505-T-A is described in ClinVar as Benign. ClinVar VariationId is 381436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1890/151616) while in subpopulation AFR AF = 0.0444 (1828/41132). AF 95% confidence interval is 0.0427. There are 48 homozygotes in GnomAd4. There are 857 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1890 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.2559T>A	p.Asp853Glu	missense	Exon 18 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.2559T>A	p.Asp853Glu	missense	Exon 18 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.2559T>A	p.Asp853Glu	missense	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.2559T>A	p.Asp853Glu	missense	Exon 18 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.2556T>A	p.Asp852Glu	missense	Exon 18 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2559T>A	p.Asp853Glu	missense	Exon 18 of 28	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1887 AN: 151502 Hom.: 48 Cov.: 27

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00769

GnomAD2 exomes AF: 0.00309 AC: 776 AN: 250920 AF XY: 0.00223

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00119 AC: 1732 AN: 1459658 Hom.: 37 Cov.: 35 AF XY: 0.00103 AC XY: 749 AN XY: 726146

African (AFR) AF: 0.0450 AC: 1501 AN: 33372

American (AMR) AF: 0.00130 AC: 58 AN: 44716

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86164

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

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4136

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111828

Other (OTH) AF: 0.00218 AC: 131 AN: 60194

GnomAD4 genome AF: 0.0125 AC: 1890 AN: 151616 Hom.: 48 Cov.: 27 AF XY: 0.0116 AC XY: 857 AN XY: 74096

African (AFR) AF: 0.0444 AC: 1828 AN: 41132

American (AMR) AF: 0.00269 AC: 41 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67942

Other (OTH) AF: 0.00761 AC: 16 AN: 2102

Alfa AF: 0.00649 Hom.: 3

Bravo AF: 0.0143

ESP6500AA AF: 0.0377 AC: 166

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00390 AC: 474

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
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.53
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.028
Sift	Benign	0.12	T
Sift4G	Benign	0.45	T
Polyphen		0.023	B
Vest4		0.15
MutPred		0.15		Gain of catalytic residue at D853 (P = 0.1918)
MVP		0.27
MPC		1.0
ClinPred		0.0039	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.24
Mutation Taster		=95/5	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: rs148999619; hg19: chr2-109374961;