rs147080366

Variant names:

• chr2-108753428-A-G
• rs147080366
• NM_006267.5:c.1920A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-108753428-A-G
• chr2-108753428-A-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006267.5(RANBP2):​c.1920A>G​(p.Ala640Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,611,734 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: RANBP2 NM_006267.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.343
• 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-108753428-A-G is Benign according to our data. Variant chr2-108753428-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 469432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.343 with no splicing effect.
• BS2: High AC in GnomAd4 at 127 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.1920A>G	p.Ala640Ala	splice_region synonymous	Exon 14 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.1920A>G	p.Ala640Ala	splice_region synonymous	Exon 14 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.1920A>G	p.Ala640Ala	splice_region synonymous	Exon 14 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.1920A>G	p.Ala640Ala	splice_region synonymous	Exon 14 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.1917A>G	p.Ala639Ala	splice_region synonymous	Exon 14 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.1920A>G	p.Ala640Ala	splice_region synonymous	Exon 14 of 28	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.000834 AC: 127 AN: 152214 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

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: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00103 AC: 231 AN: 225206 AF XY: 0.000991

Gnomad AFR exome AF: 0.000285

Gnomad AMR exome AF: 0.000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00336

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.00107 AC: 1568 AN: 1459402 Hom.: 1 Cov.: 34 AF XY: 0.00109 AC XY: 790 AN XY: 726018

African (AFR) AF: 0.000240 AC: 8 AN: 33398

American (AMR) AF: 0.000224 AC: 10 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86152

European-Finnish (FIN) AF: 0.00376 AC: 201 AN: 53416

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4132

European-Non Finnish (NFE) AF: 0.00116 AC: 1292 AN: 1111702

Other (OTH) AF: 0.000847 AC: 51 AN: 60182

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152332 Hom.: 0 Cov.: 31 AF XY: 0.000873 AC XY: 65 AN XY: 74488

African (AFR) AF: 0.000168 AC: 7 AN: 41580

American (AMR) AF: 0.000327 AC: 5 AN: 15306

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: 4828

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000800 Hom.: 0

Bravo AF: 0.000778

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Familial acute necrotizing encephalopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.4
DANN	Benign	0.76
PhyloP100		-0.34
Mutation Taster		=93/7	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: rs147080366; hg19: chr2-109369884;