NM_006267.5:c.5249C>G

Variant names:

• chr2-108765788-C-G
• rs1060499624
• NM_006267.5:c.5249C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_006267.5(RANBP2):​c.5249C>G​(p.Pro1750Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.847

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-108765788-C-G is Pathogenic according to our data. Variant chr2-108765788-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 393529.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.5249C>G	p.Pro1750Arg	missense_variant	Exon 20 of 29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.5249C>G	p.Pro1750Arg	missense_variant	Exon 20 of 29	1	NM_006267.5	ENSP00000283195.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial acute necrotizing encephalopathy Pathogenic:1

Oct 28, 2016

Kamineni Academy of Medical Sciences & Research Centre, Kamineni Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.64		Gain of MoRF binding (P = 0.0174);
MVP		0.60
MPC		1.1
ClinPred		0.81	D
GERP RS		2.4
Varity_R		0.20
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060499624; hg19: chr2-109382244;