rs142768885

Positions:

• chr2-108763765-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The ENST00000283195.11(RANBP2):​c.3226T>G​(p.Leu1076Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,942 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: RANBP2 ENST00000283195.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.0590

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 -8 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=0.025209308).
• BP6: Variant 2-108763765-T-G is Benign according to our data. Variant chr2-108763765-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 417861.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}. Variant chr2-108763765-T-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.3226T>G	p.Leu1076Val	missense_variant	20/29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.3226T>G	p.Leu1076Val	missense_variant	20/29	1	NM_006267.5	ENSP00000283195	P1
RANBP2	ENST00000697737.1	c.2602+5217T>G		intron_variant				ENSP00000513426
RANBP2	ENST00000697740.1	c.2524+5217T>G		intron_variant				ENSP00000513427

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000455 AC: 114 AN: 250660 Hom.: 0 AF XY: 0.000494 AC XY: 67 AN XY: 135626

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000891

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.00108 AC: 1574 AN: 1461794 Hom.: 2 Cov.: 34 AF XY: 0.00102 AC XY: 739 AN XY: 727200

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000605 AC: 92 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74338

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000986 Hom.: 0

Bravo AF: 0.000627

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.00115

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 08, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial acute necrotizing encephalopathy Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.3226T>G (p.L1076V) alteration is located in exon 20 (coding exon 20) of the RANBP2 gene. This alteration results from a T to G substitution at nucleotide position 3226, causing the leucine (L) at amino acid position 1076 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.083
Sift	Benign	0.20	T
Sift4G	Benign	0.11	T
Polyphen		0.0060	B
Vest4		0.11
MVP		0.60
MPC		0.36
ClinPred		0.011	T
GERP RS		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.10

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: rs142768885; hg19: chr2-109380221;