chr2-108740483-T-C

Variant names:

• chr2-108740483-T-C
• rs138540027
• NM_006267.5:c.783-6T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006267.5(RANBP2):​c.783-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,597,564 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (5 hom.)
• Consequence: RANBP2 NM_006267.5 splice_region, intron
• Scores: Splicing: ADA: 0.003552
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.70
• 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, 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-108740483-T-C is Benign according to our data. Variant chr2-108740483-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 383037.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High AC in GnomAd4 at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.783-6T>C		splice_region_variant, intron_variant	Intron 6 of 28	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.783-6T>C		splice_region_variant, intron_variant	Intron 6 of 28	1	NM_006267.5	ENSP00000283195.6

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152240 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00112 AC: 267 AN: 238508 AF XY: 0.00113

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00161

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.00183 AC: 2640 AN: 1445206 Hom.: 5 Cov.: 32 AF XY: 0.00180 AC XY: 1295 AN XY: 719330

African (AFR) AF: 0.000240 AC: 8 AN: 33402

American (AMR) AF: 0.000313 AC: 14 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00179 AC: 154 AN: 86162

European-Finnish (FIN) AF: 0.00135 AC: 53 AN: 39142

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4134

European-Non Finnish (NFE) AF: 0.00211 AC: 2344 AN: 1111728

Other (OTH) AF: 0.00108 AC: 65 AN: 60118

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152358 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74506

African (AFR) AF: 0.000240 AC: 10 AN: 41594

American (AMR) AF: 0.00137 AC: 21 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000754 Hom.: 0

Bravo AF: 0.000937

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RANBP2: BS1, BS2 -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 21, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.783-6 T>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.783-6 T>C variant is observed in 106/64806 (0.16%) alleles from individuals of European background, including 1 homozygous individual in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.783-6 T>C substitution occurs at a position that is conserved across species. In-silico splice prediction models are inconsistent in their predictions as to whether or not c.783-6 T>C results in abnormal gene splicing, and in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial acute necrotizing encephalopathy Benign:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	14
DANN	Benign	0.69
PhyloP100		1.7
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0036
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.080		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: rs138540027; hg19: chr2-109356939;