rs2912838

Variant names:

• chr2-108755053-G-A
• rs2912838
• NM_006267.5:c.2351G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006267.5(RANBP2):​c.2351G>A​(p.Arg784Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,610,890 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 30)
  • Exomes 𝑓: 0.00089 (37 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.12
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00420475).
• BP6: Variant 2-108755053-G-A is Benign according to our data. Variant chr2-108755053-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00658 (1001/152118) while in subpopulation AFR AF = 0.0208 (860/41430). AF 95% confidence interval is 0.0196. There are 9 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1001 AD gene.

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.2351G>A	p.Arg784Lys	missense	Exon 16 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.2351G>A	p.Arg784Lys	missense	Exon 16 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.2351G>A	p.Arg784Lys	missense	Exon 16 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.2351G>A	p.Arg784Lys	missense	Exon 16 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.2348G>A	p.Arg783Lys	missense	Exon 16 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2351G>A	p.Arg784Lys	missense	Exon 16 of 28	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1002 AN: 152000 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00119 AC: 297 AN: 249486 AF XY: 0.000784

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000872

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000893 AC: 1303 AN: 1458772 Hom.: 37 Cov.: 32 AF XY: 0.000812 AC XY: 589 AN XY: 725766

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

African (AFR) AF: 0.0119 AC: 391 AN: 32814

American (AMR) AF: 0.00150 AC: 67 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0177 AC: 701 AN: 39614

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86152

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00218 AC: 9 AN: 4134

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111706

Other (OTH) AF: 0.000998 AC: 60 AN: 60148

⚠️ 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: 0.00658 AC: 1001 AN: 152118 Hom.: 9 Cov.: 30 AF XY: 0.00625 AC XY: 465 AN XY: 74374

African (AFR) AF: 0.0208 AC: 860 AN: 41430

American (AMR) AF: 0.00425 AC: 65 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00946 AC: 49 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68012

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00443 Hom.: 1

Bravo AF: 0.00791

ExAC AF: 0.00191 AC: 232

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Familial acute necrotizing encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.2
DANN	Benign	0.41
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.8	N
PhyloP100		2.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.099
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.096
MVP		0.15
MPC		1.0
ClinPred		0.0012	T
GERP RS		0.33
Varity_R		0.024
gMVP		0.26
Mutation Taster		=99/1	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: rs2912838; hg19: chr2-109371509; COSMIC: COSV51706434; COSMIC: COSV51706434;