2-108719562-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006267.5(RANBP2):c.-45C>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 0.034 in 1,578,448 control chromosomes in the GnomAD database, including 1,001 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (70 hom., cov: 32)
  • Exomes 𝑓: 0.035 (931 hom.)
• Consequence: RANBP2 NM_006267.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.60

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=-0.76).
• BP6: Variant 2-108719562-C-T is Benign according to our data. Variant chr2-108719562-C-T is described in ClinVar as [Benign]. Clinvar id is 380075.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0229 (3487/152388) while in subpopulation NFE AF= 0.0364 (2473/68032). AF 95% confidence interval is 0.0352. There are 70 homozygotes in gnomad4. There are 1591 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3487 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.-45C>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.-45C>T		5_prime_UTR_variant	1/29	1	NM_006267.5	P1
RANBP2	ENST00000697737.1	c.-45C>T		5_prime_UTR_variant	1/27
RANBP2	ENST00000697738.1	n.65C>T		non_coding_transcript_exon_variant	1/10
RANBP2	ENST00000425282.4	c.-45C>T		5_prime_UTR_variant, NMD_transcript_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3487 AN: 152270 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00750

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0351

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0256 AC: 4997 AN: 195412 Hom.: 76 AF XY: 0.0274 AC XY: 2889 AN XY: 105420

Gnomad AFR exome AF: 0.00604

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.000139

Gnomad SAS exome AF: 0.0387

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0352 AC: 50143 AN: 1426060 Hom.: 931 Cov.: 30 AF XY: 0.0356 AC XY: 25172 AN XY: 706168

Gnomad4 AFR exome AF: 0.00513

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.000131

Gnomad4 SAS exome AF: 0.0380

Gnomad4 FIN exome AF: 0.0225

Gnomad4 NFE exome AF: 0.0394

Gnomad4 OTH exome AF: 0.0291

GnomAD4 genome AF: 0.0229 AC: 3487 AN: 152388 Hom.: 70 Cov.: 32 AF XY: 0.0213 AC XY: 1591 AN XY: 74522

Gnomad4 AFR AF: 0.00748

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0350

Gnomad4 FIN AF: 0.0175

Gnomad4 NFE AF: 0.0364

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0183 Hom.: 13

Bravo AF: 0.0220

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	10
Dann	Benign	0.78

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: rs79379002; hg19: chr2-109336018;