chr2-108719566-G-T

Position:

• chr2-108719566-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006267.5(RANBP2):​c.-41G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,582,444 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (18 hom.)
• Consequence: RANBP2 NM_006267.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0740

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-108719566-G-T is Benign according to our data. Variant chr2-108719566-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 382095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 485 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.-41G>T		5_prime_UTR_variant	1/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.-41G>T		5_prime_UTR_variant	1/29	1	NM_006267.5	P1
RANBP2	ENST00000697737.1	c.-41G>T		5_prime_UTR_variant	1/27
RANBP2	ENST00000697738.1	n.69G>T		non_coding_transcript_exon_variant	1/10
RANBP2	ENST00000425282.4	c.-41G>T		5_prime_UTR_variant, NMD_transcript_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 485 AN: 152270 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00586

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00282 AC: 568 AN: 201230 Hom.: 2 AF XY: 0.00261 AC XY: 284 AN XY: 108716

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.000631

Gnomad ASJ exome AF: 0.00212

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000542

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00448 AC: 6410 AN: 1430056 Hom.: 18 Cov.: 30 AF XY: 0.00437 AC XY: 3096 AN XY: 708540

Gnomad4 AFR exome AF: 0.000757

Gnomad4 AMR exome AF: 0.000764

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.000757

Gnomad4 FIN exome AF: 0.00214

Gnomad4 NFE exome AF: 0.00543

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.00318 AC: 485 AN: 152388 Hom.: 1 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74526

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00263

Gnomad4 NFE AF: 0.00586

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00288 Hom.: 1

Bravo AF: 0.00296

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

not provided Benign:1

Likely 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	-0.80
CADD	Benign	3.4
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs372373398; hg19: chr2-109336022;