2-108768392-A-G

Position:

• chr2-108768392-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006267.5(RANBP2):​c.7849+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00469 in 1,599,878 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (111 hom.)
• Consequence: RANBP2 NM_006267.5 splice_region, intron
• Scores: Splicing: ADA: 0.03582
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.98

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-108768392-A-G is Benign according to our data. Variant chr2-108768392-A-G is described in ClinVar as [Benign]. Clinvar id is 382464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108768392-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00582 (886/152106) while in subpopulation SAS AF= 0.0211 (102/4832). AF 95% confidence interval is 0.0178. There are 5 homozygotes in gnomad4. There are 450 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 886 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.7849+4A>G		splice_region_variant, intron_variant		ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.7849+4A>G		splice_region_variant, intron_variant		1	NM_006267.5	ENSP00000283195.6

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 885 AN: 151988 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.0202

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00685

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00479 AC: 1169 AN: 243906 Hom.: 20 AF XY: 0.00465 AC XY: 618 AN XY: 132912

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.00259

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.0159

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00457 AC: 6620 AN: 1447772 Hom.: 111 Cov.: 33 AF XY: 0.00488 AC XY: 3512 AN XY: 720314

Gnomad4 AFR exome AF: 0.000719

Gnomad4 AMR exome AF: 0.00267

Gnomad4 ASJ exome AF: 0.00516

Gnomad4 EAS exome AF: 0.0301

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.000648

Gnomad4 NFE exome AF: 0.00327

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00582 AC: 886 AN: 152106 Hom.: 5 Cov.: 32 AF XY: 0.00605 AC XY: 450 AN XY: 74406

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00837

Gnomad4 EAS AF: 0.0202

Gnomad4 SAS AF: 0.0211

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00686

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00661 Hom.: 3

Bravo AF: 0.00662

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial acute necrotizing encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.036
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.010		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: rs2949961; hg19: chr2-109384848; COSMIC: COSV51696919;