rs121434504

Variant names:

• chr2-108753474-A-G
• rs121434504
• NM_006267.5:c.1966A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_006267.5(RANBP2):​c.1966A>G​(p.Ile656Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,572 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I656T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 O:2
• Conservation: PhyloP100: 1.04
• Publications: 15 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-108753474-A-G is Pathogenic according to our data. Variant chr2-108753474-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8365.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.1966A>G	p.Ile656Val	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.1966A>G	p.Ile656Val	missense_variant	Exon 14 of 29	1	NM_006267.5	ENSP00000283195.6
RANBP2	ENST00000697737.1	c.1966A>G	p.Ile656Val	missense_variant	Exon 14 of 27			ENSP00000513426.1
RANBP2	ENST00000697740.1	c.1888A>G	p.Ile630Val	missense_variant	Exon 14 of 27			ENSP00000513427.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459572 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726092

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60196

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial acute necrotizing encephalopathy Pathogenic:2 Uncertain:1 Other:2

Sep 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 656 of the RANBP2 protein (p.Ile656Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with acute necrotizing encephalopathy (PMID: 19118815, 22030434). This variant is also known as c.2094A>G, g.33868A>G. ClinVar contains an entry for this variant (Variation ID: 8365). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 01, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 15, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 31, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with acute necrotizing encephalopathy in published literature (PMID: 19118815, 22030434, 37093442); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37093442, 32493103, 22030434, 33726816, Werner[2022]abstract, 35408907, 36029610, 36572756, 33600493, 19118815, 35679405) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.49
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0041	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.17	N
PhyloP100		1.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.17	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.71
MutPred		0.77		Loss of sheet (P = 0.003);
MVP		0.95
MPC		0.89
ClinPred		0.041	T
GERP RS		-0.48
Varity_R		0.021
gMVP		0.17
Mutation Taster		=45/55	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: rs121434504; hg19: chr2-109369930;