2-108758496-A-G

Position:

• chr2-108758496-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006267.5(RANBP2):​c.2550A>G​(p.Ser850Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 150,522 control chromosomes in the GnomAD database, including 12,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (12730 hom., cov: 27)
  • Exomes 𝑓: 0.25 (49902 hom.)
  • Failed GnomAD Quality Control
• Consequence: RANBP2 NM_006267.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.202

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-108758496-A-G is Benign according to our data. Variant chr2-108758496-A-G is described in ClinVar as [Benign]. Clinvar id is 380029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.202 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.2550A>G	p.Ser850Ser	synonymous_variant	18/29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.2550A>G	p.Ser850Ser	synonymous_variant	18/29	1	NM_006267.5	ENSP00000283195.6
RANBP2	ENST00000697737.1	c.2550A>G	p.Ser850Ser	synonymous_variant	18/27			ENSP00000513426.1
RANBP2	ENST00000697740.1	c.2472A>G	p.Ser824Ser	synonymous_variant	18/27			ENSP00000513427.1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53075 AN: 150404 Hom.: 12680 Cov.: 27

Gnomad AFR AF: 0.685

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.0700

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.312

GnomAD3 exomes AF: 0.246 AC: 61490 AN: 249652 Hom.: 10250 AF XY: 0.246 AC XY: 33289 AN XY: 135134

Gnomad AFR exome AF: 0.699

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.0455

Gnomad SAS exome AF: 0.322

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.244

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.248 AC: 360529 AN: 1456270 Hom.: 49902 Cov.: 40 AF XY: 0.249 AC XY: 180793 AN XY: 724664

Gnomad4 AFR exome AF: 0.708

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.0969

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.267

GnomAD4 genome AF: 0.353 AC: 53188 AN: 150522 Hom.: 12730 Cov.: 27 AF XY: 0.347 AC XY: 25551 AN XY: 73562

Gnomad4 AFR AF: 0.686

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.0698

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.319

Alfa AF: 0.294 Hom.: 1514

Bravo AF: 0.372

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 05, 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 23, 2024

- -

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	-0.83
CADD	Benign	6.4
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs826549; hg19: chr2-109374952; COSMIC: COSV51697984;