chr2-108719689-C-G

Position:

• chr2-108719689-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006267.5(RANBP2):​c.72+11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00875 in 1,597,440 control chromosomes in the GnomAD database, including 911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (482 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (429 hom.)
• Consequence: RANBP2 NM_006267.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-108719689-C-G is Benign according to our data. Variant chr2-108719689-C-G is described in ClinVar as [Benign]. Clinvar id is 380105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108719689-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.72+11C>G		intron_variant		ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.72+11C>G		intron_variant		1	NM_006267.5	P1
RANBP2	ENST00000697737.1	c.72+11C>G		intron_variant
RANBP2	ENST00000425282.4	c.72+11C>G		intron_variant, NMD_transcript_variant		5
RANBP2	ENST00000697738.1	n.181+11C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6534 AN: 152210 Hom.: 480 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0310

GnomAD3 exomes AF: 0.0123 AC: 2718 AN: 221162 Hom.: 161 AF XY: 0.00941 AC XY: 1128 AN XY: 119912

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00609

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000505

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.00764

GnomAD4 exome AF: 0.00514 AC: 7421 AN: 1445114 Hom.: 429 Cov.: 30 AF XY: 0.00455 AC XY: 3264 AN XY: 717536

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.00545

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000370

Gnomad4 FIN exome AF: 0.0000579

Gnomad4 NFE exome AF: 0.000753

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0430 AC: 6551 AN: 152326 Hom.: 482 Cov.: 32 AF XY: 0.0414 AC XY: 3084 AN XY: 74486

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.00400 Hom.: 1

Bravo AF: 0.0494

Asia WGS AF: 0.0120 AC: 41 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 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

Oct 03, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.0
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs113447280; hg19: chr2-109336145;