rs550357048

Variant names:

• chr2-108766970-G-A
• rs550357048
• NM_006267.5:c.6431G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_006267.5(RANBP2):​c.6431G>A​(p.Arg2144Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000466 in 1,609,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2144W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.84
• Publications: 0 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, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20904681).
• BS2: High AC in GnomAd4 at 13 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006267.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	NM_006267.5	MANE Select	c.6431G>A	p.Arg2144Gln	missense	Exon 20 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.6431G>A	p.Arg2144Gln	missense	Exon 20 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.6431G>A	p.Arg2144Gln	missense	Exon 20 of 29	NP_001402802.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.6431G>A	p.Arg2144Gln	missense	Exon 20 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.6428G>A	p.Arg2143Gln	missense	Exon 20 of 29	ENSP00000588042.1
	RANBP2	ENST00000697745.1		c.1295G>A	p.Arg432Gln	missense	Exon 1 of 10	ENSP00000513429.1	A0A8V8TLN4

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000710 AC: 17 AN: 239450 AF XY: 0.0000457

Gnomad AFR exome AF: 0.0000696

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000426 AC: 62 AN: 1456954 Hom.: 0 Cov.: 33 AF XY: 0.0000331 AC XY: 24 AN XY: 724944

African (AFR) AF: 0.000120 AC: 4 AN: 33400

American (AMR) AF: 0.000358 AC: 16 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50726

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111806

Other (OTH) AF: 0.0000498 AC: 3 AN: 60192

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74444

African (AFR) AF: 0.000169 AC: 7 AN: 41538

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000336 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Familial acute necrotizing encephalopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N
PhyloP100		5.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Benign	0.18	T
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.42		Gain of helix (P = 0.0696)
MVP		0.56
MPC		1.2
ClinPred		0.10	T
GERP RS		5.3
Varity_R		0.095
gMVP		0.41
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs550357048; hg19: chr2-109383426;