2-108729126-T-A

Position:

• chr2-108729126-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006267.5(RANBP2):​c.73-6T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00611 in 1,570,198 control chromosomes in the GnomAD database, including 52 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (39 hom.)
• Consequence: RANBP2 NM_006267.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.8400
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.02

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-108729126-T-A is Benign according to our data. Variant chr2-108729126-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 446012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108729126-T-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 754 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.73-6T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.73-6T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.00495 AC: 754 AN: 152242 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00449 AC: 1028 AN: 229084 Hom.: 7 AF XY: 0.00431 AC XY: 539 AN XY: 125026

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.00673

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000950

Gnomad FIN exome AF: 0.000515

Gnomad NFE exome AF: 0.00635

Gnomad OTH exome AF: 0.00708

GnomAD4 exome AF: 0.00624 AC: 8845 AN: 1417838 Hom.: 39 Cov.: 31 AF XY: 0.00606 AC XY: 4271 AN XY: 705206

Gnomad4 AFR exome AF: 0.000977

Gnomad4 AMR exome AF: 0.00695

Gnomad4 ASJ exome AF: 0.00219

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000987

Gnomad4 FIN exome AF: 0.000682

Gnomad4 NFE exome AF: 0.00732

Gnomad4 OTH exome AF: 0.00578

GnomAD4 genome AF: 0.00495 AC: 754 AN: 152360 Hom.: 13 Cov.: 32 AF XY: 0.00454 AC XY: 338 AN XY: 74512

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00452 Hom.: 2

Bravo AF: 0.00605

EpiCase AF: 0.00845

EpiControl AF: 0.00760

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	RANBP2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 31, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 17, 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.51
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: rs201485597; hg19: chr2-109345582;