rs826549

Variant names:

• chr2-108758496-A-G
• rs826549
• NM_006267.5:c.2550A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

RANBP2 Gene-Disease associations (from GenCC):

• familial acute necrotizing encephalopathy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.2550A>G	p.Ser850Ser	synonymous_variant	Exon 18 of 29	ENST00000283195.11	NP_006258.3

Ensembl

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

GnomAD2 exomes AF: 0.246 AC: 61490 AN: 249652 AF XY: 0.246

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.708 AC: 23520 AN: 33228

American (AMR) AF: 0.163 AC: 7279 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6414 AN: 26110

East Asian (EAS) AF: 0.0969 AC: 3845 AN: 39692

South Asian (SAS) AF: 0.329 AC: 28286 AN: 86048

European-Finnish (FIN) AF: 0.192 AC: 10232 AN: 53416

Middle Eastern (MID) AF: 0.288 AC: 1188 AN: 4128

European-Non Finnish (NFE) AF: 0.238 AC: 263736 AN: 1108874

Other (OTH) AF: 0.267 AC: 16029 AN: 60072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.686 AC: 27835 AN: 40586

American (AMR) AF: 0.245 AC: 3707 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 853 AN: 3460

East Asian (EAS) AF: 0.0698 AC: 360 AN: 5160

South Asian (SAS) AF: 0.335 AC: 1582 AN: 4722

European-Finnish (FIN) AF: 0.180 AC: 1885 AN: 10474

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 15973 AN: 67714

Other (OTH) AF: 0.319 AC: 664 AN: 2082

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

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.64
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs826549; hg19: chr2-109374952; COSMIC: COSV51697984;