rs372373398

Variant names:

• chr2-108719566-G-T
• rs372373398
• NM_006267.5:c.-41G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-108719566-G-T
• chr2-108719566-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006267.5(RANBP2):​c.-41G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,582,444 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (18 hom.)
• Consequence: RANBP2 NM_006267.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0740
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-108719566-G-T is Benign according to our data. Variant chr2-108719566-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 382095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 485 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.-41G>T		5_prime_UTR	Exon 1 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.-41G>T		5_prime_UTR	Exon 1 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.-41G>T		5_prime_UTR	Exon 1 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.-41G>T		5_prime_UTR	Exon 1 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.-41G>T		5_prime_UTR	Exon 1 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.-41G>T		5_prime_UTR	Exon 1 of 28	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 485 AN: 152270 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00586

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00282 AC: 568 AN: 201230 AF XY: 0.00261

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.000631

Gnomad ASJ exome AF: 0.00212

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00448 AC: 6410 AN: 1430056 Hom.: 18 Cov.: 30 AF XY: 0.00437 AC XY: 3096 AN XY: 708540

African (AFR) AF: 0.000757 AC: 25 AN: 33014

American (AMR) AF: 0.000764 AC: 30 AN: 39246

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 39 AN: 25432

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38472

South Asian (SAS) AF: 0.000757 AC: 62 AN: 81948

European-Finnish (FIN) AF: 0.00214 AC: 108 AN: 50452

Middle Eastern (MID) AF: 0.000488 AC: 2 AN: 4102

European-Non Finnish (NFE) AF: 0.00543 AC: 5965 AN: 1098176

Other (OTH) AF: 0.00301 AC: 178 AN: 59214

GnomAD4 genome AF: 0.00318 AC: 485 AN: 152388 Hom.: 1 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74526

African (AFR) AF: 0.000866 AC: 36 AN: 41594

American (AMR) AF: 0.000914 AC: 14 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00263 AC: 28 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00586 AC: 399 AN: 68042

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00288 Hom.: 1

Bravo AF: 0.00296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.4
DANN	Benign	0.66
PhyloP100		-0.074
PromoterAI		0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=299/1	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: rs372373398; hg19: chr2-109336022;