NM_006267.5:c.1632-10_1632-1delTATTTTTTAGinsAATTTTTAT

Variant names:

• chr2-108751861-TATTTTTTAG-AATTTTTAT
• rs1553489293
• NM_006267.5:c.1632-10_1632-1delTATTTTTTAGinsAATTTTTAT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_006267.5(RANBP2):​c.1632-10_1632-1delTATTTTTTAGinsAATTTTTAT variant causes a splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RANBP2 NM_006267.5 splice_acceptor, splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.45
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012816537 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of -33, new splice context is: gccctgaactgtgtatttAGaaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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.1632-10_1632-1delTATTTTTTAGinsAATTTTTAT		splice_acceptor splice_region intron	N/A	NP_006258.3
	RANBP2	NM_001415871.1		c.1632-10_1632-1delTATTTTTTAGinsAATTTTTAT		splice_acceptor splice_region intron	N/A	NP_001402800.1
	RANBP2	NM_001415873.1		c.1632-10_1632-1delTATTTTTTAGinsAATTTTTAT		splice_acceptor splice_region intron	N/A	NP_001402802.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.1632-10_1632-1delTATTTTTTAGinsAATTTTTAT		splice_acceptor splice_region intron	N/A	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.1629-10_1629-1delTATTTTTTAGinsAATTTTTAT		splice_acceptor splice_region intron	N/A	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.1632-10_1632-1delTATTTTTTAGinsAATTTTTAT		splice_acceptor splice_region intron	N/A	ENSP00000630145.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

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
PhyloP100		6.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553489293; hg19: chr2-109368317;