rs376940698

Positions:

• chr2-108781340-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_006267.5(RANBP2):​c.8671G>A​(p.Gly2891Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,614,152 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (13 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.615

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 -9 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RANBP2. . Gene score misZ -0.77637 (greater than the threshold 3.09). Trascript score misZ 3.8106 (greater than threshold 3.09). GenCC has associacion of gene with Leigh syndrome, familial acute necrotizing encephalopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043631196).
• BP6: Variant 2-108781340-G-A is Benign according to our data. Variant chr2-108781340-G-A is described in ClinVar as [Benign]. Clinvar id is 537230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.8671G>A	p.Gly2891Ser	missense_variant	26/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.8671G>A	p.Gly2891Ser	missense_variant	26/29	1	NM_006267.5	P1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000903 AC: 227 AN: 251440 Hom.: 3 AF XY: 0.00124 AC XY: 168 AN XY: 135898

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000536 AC: 784 AN: 1461876 Hom.: 13 Cov.: 31 AF XY: 0.000751 AC XY: 546 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.00693

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000971 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00107 AC: 130

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial acute necrotizing encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.4
DANN	Benign	0.20
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.021
Sift	Benign	0.58	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.094
MVP		0.15
MPC		0.35
ClinPred		0.0042	T
GERP RS		0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.099

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: rs376940698; hg19: chr2-109397796;