rs121434503

Variant names:

• chr2-108753466-C-T
• rs121434503
• NM_006267.5:c.1958C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006267.5(RANBP2):​c.1958C>T​(p.Thr653Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T653A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: risk factor no assertion criteria provided O:2
• Conservation: PhyloP100: 4.04
• Publications: 14 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, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.1958C>T	p.Thr653Ile	missense_variant	Exon 14 of 29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.1958C>T	p.Thr653Ile	missense_variant	Exon 14 of 29	1	NM_006267.5	ENSP00000283195.6
RANBP2	ENST00000697737.1	c.1958C>T	p.Thr653Ile	missense_variant	Exon 14 of 27			ENSP00000513426.1
RANBP2	ENST00000697740.1	c.1880C>T	p.Thr627Ile	missense_variant	Exon 14 of 27			ENSP00000513427.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: risk factor

Submissions summary: Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Familial acute necrotizing encephalopathy Other:2

Jan 01, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.35	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.66	P
Vest4		0.86
MutPred		0.78		Loss of helix (P = 3e-04);
MVP		0.88
MPC		1.2
ClinPred		0.74	D
GERP RS		4.0
Varity_R		0.066
gMVP		0.45
Mutation Taster		=79/21	disease causing (ClinVar)

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: rs121434503; hg19: chr2-109369922;