rs111676038

Variant names:

• chr2-108765069-A-G
• rs111676038
• NM_006267.5:c.4530A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-108765069-A-G
• chr2-108765069-A-C
• chr2-108765069-A-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006267.5(RANBP2):​c.4530A>G​(p.Leu1510Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,614,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: RANBP2 NM_006267.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.800
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-108765069-A-G is Benign according to our data. Variant chr2-108765069-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 469461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.8 with no splicing effect.
• BS2: High AC in GnomAd4 at 149 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.4530A>G	p.Leu1510Leu	synonymous	Exon 20 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.4530A>G	p.Leu1510Leu	synonymous	Exon 20 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.4530A>G	p.Leu1510Leu	synonymous	Exon 20 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.4530A>G	p.Leu1510Leu	synonymous	Exon 20 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.4527A>G	p.Leu1509Leu	synonymous	Exon 20 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2603-4191A>G		intron	N/A	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 149 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000307 AC: 77 AN: 250980 AF XY: 0.000273

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000153 AC: 224 AN: 1461766 Hom.: 1 Cov.: 36 AF XY: 0.000154 AC XY: 112 AN XY: 727178

African (AFR) AF: 0.00454 AC: 152 AN: 33466

American (AMR) AF: 0.000179 AC: 8 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111948

Other (OTH) AF: 0.000695 AC: 42 AN: 60392

GnomAD4 genome AF: 0.000978 AC: 149 AN: 152314 Hom.: 0 Cov.: 31 AF XY: 0.00101 AC XY: 75 AN XY: 74474

African (AFR) AF: 0.00339 AC: 141 AN: 41564

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

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

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.00119

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/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	-0.86
CADD	Benign	0.25
DANN	Benign	0.28
PhyloP100		-0.80
Mutation Taster		=100/0	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: rs111676038; hg19: chr2-109381525;