NM_006267.5:c.7172C>G

Variant names:

• chr2-108767711-C-G
• rs2433786
• NM_006267.5:c.7172C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_006267.5(RANBP2):​c.7172C>G​(p.Thr2391Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0041 in 1,596,446 control chromosomes in the GnomAD database, including 79 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (78 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.22
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021814346).
• BP6: Variant 2-108767711-C-G is Benign according to our data. Variant chr2-108767711-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 469482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.7172C>G	p.Thr2391Ser	missense	Exon 20 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.7172C>G	p.Thr2391Ser	missense	Exon 20 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.7172C>G	p.Thr2391Ser	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.7172C>G	p.Thr2391Ser	missense	Exon 20 of 29	ENSP00000283195.6
	RANBP2	ENST00000697745.1		c.2036C>G	p.Thr679Ser	missense	Exon 1 of 10	ENSP00000513429.1
	RANBP2	ENST00000697744.1		n.2036C>G		non_coding_transcript_exon	Exon 1 of 11	ENSP00000513428.1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 782 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00877

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00117 AC: 292 AN: 248974 AF XY: 0.00115

Gnomad AFR exome AF: 0.000588

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.00399 AC: 5765 AN: 1444280 Hom.: 78 Cov.: 33 AF XY: 0.00389 AC XY: 2794 AN XY: 718696

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

African (AFR) AF: 0.000900 AC: 30 AN: 33342

American (AMR) AF: 0.00242 AC: 108 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.000996 AC: 26 AN: 26098

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39696

South Asian (SAS) AF: 0.000755 AC: 65 AN: 86056

European-Finnish (FIN) AF: 0.00330 AC: 176 AN: 53258

Middle Eastern (MID) AF: 0.00218 AC: 9 AN: 4132

European-Non Finnish (NFE) AF: 0.00464 AC: 5097 AN: 1097364

Other (OTH) AF: 0.00417 AC: 249 AN: 59768

⚠️ 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: 0.00514 AC: 782 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74412

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

African (AFR) AF: 0.00176 AC: 73 AN: 41542

American (AMR) AF: 0.00399 AC: 61 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00321 AC: 34 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00877 AC: 596 AN: 67946

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

⚠️ 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: 0.00227 Hom.: 0

ExAC AF: 0.000107 AC: 13

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Familial acute necrotizing encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.042	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.17
Sift	Benign	0.50	T
Sift4G	Benign	0.16	T
Polyphen		0.27	B
Vest4		0.24
MutPred		0.47		Gain of disorder (P = 0.0687)
MVP		0.60
MPC		0.36
ClinPred		0.025	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.056
gMVP		0.10
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: rs2433786; hg19: chr2-109384167; COSMIC: COSV51706519;