rs200438979

Variant names:

• chr2-108768344-C-T
• rs200438979
• NM_006267.5:c.7805C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006267.5(RANBP2):​c.7805C>T​(p.Thr2602Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000437 in 1,610,048 control chromosomes in the GnomAD database, including 2 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.47
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0142250955).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	NM_006267.5	MANE Select	c.7805C>T	p.Thr2602Met	missense	Exon 20 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.7805C>T	p.Thr2602Met	missense	Exon 20 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.7805C>T	p.Thr2602Met	missense	Exon 20 of 29	NP_001402802.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.7805C>T	p.Thr2602Met	missense	Exon 20 of 29	ENSP00000283195.6
	RANBP2	ENST00000697745.1		c.2669C>T	p.Thr890Met	missense	Exon 1 of 10	ENSP00000513429.1
	RANBP2	ENST00000697747.1		c.434C>T	p.Thr145Met	missense	Exon 1 of 11	ENSP00000513430.1

Frequencies

GnomAD3 genomes AF: 0.000724 AC: 110 AN: 151866 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00106 AC: 261 AN: 247298 AF XY: 0.00101

Gnomad AFR exome AF: 0.000405

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.000407 AC: 593 AN: 1458064 Hom.: 2 Cov.: 33 AF XY: 0.000440 AC XY: 319 AN XY: 725398

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

African (AFR) AF: 0.000150 AC: 5 AN: 33394

American (AMR) AF: 0.000246 AC: 11 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26112

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39688

South Asian (SAS) AF: 0.000975 AC: 84 AN: 86152

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53356

Middle Eastern (MID) AF: 0.00363 AC: 15 AN: 4132

European-Non Finnish (NFE) AF: 0.000351 AC: 390 AN: 1110430

Other (OTH) AF: 0.000682 AC: 41 AN: 60134

⚠️ 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: 0.000724 AC: 110 AN: 151984 Hom.: 0 Cov.: 31 AF XY: 0.000619 AC XY: 46 AN XY: 74338

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

African (AFR) AF: 0.000313 AC: 13 AN: 41536

American (AMR) AF: 0.000458 AC: 7 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5174

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 67788

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00175 Hom.: 0

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000352 AC: 3

ExAC AF: 0.00135 AC: 163

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.050
Sift	Benign	0.22	T
Sift4G	Uncertain	0.026	D
Polyphen		0.66	P
Vest4		0.15
MVP		0.35
MPC		0.77
ClinPred		0.023	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.31
Mutation Taster		=97/3	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: rs200438979; hg19: chr2-109384800;