rs149826319

Variant names:

• chr2-108763574-G-T
• rs149826319
• NM_006267.5:c.3035G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-108763574-G-T
• chr2-108763574-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006267.5(RANBP2):​c.3035G>T​(p.Gly1012Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2261422).
• BS2: High AC in GnomAdExome4 at 22 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.3035G>T	p.Gly1012Val	missense	Exon 20 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.3035G>T	p.Gly1012Val	missense	Exon 20 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.3035G>T	p.Gly1012Val	missense	Exon 20 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.3035G>T	p.Gly1012Val	missense	Exon 20 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.3032G>T	p.Gly1011Val	missense	Exon 20 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2602+5026G>T		intron	N/A	ENSP00000630145.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251172 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461838 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial acute necrotizing encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.16
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.67	P
Vest4		0.43
MutPred		0.13		Loss of relative solvent accessibility (P = 0.0981)
MVP		0.34
MPC		0.44
ClinPred		0.14	T
GERP RS		2.4
Varity_R		0.10
gMVP		0.35
Mutation Taster		=77/23	polymorphism

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: rs149826319; hg19: chr2-109380030;