2-108763950-A-C

Variant names:

• chr2-108763950-A-C
• rs76461420
• NM_006267.5:c.3411A>C

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.3411A>C​(p.Pro1137Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,614,010 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (8 hom., cov: 31)
  • Exomes 𝑓: 0.010 (95 hom.)
• Consequence: RANBP2 NM_006267.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.128
• Publications: 2 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=-0.93).
• BP6: Variant 2-108763950-A-C is Benign according to our data. Variant chr2-108763950-A-C is described in ClinVar as Benign. ClinVar VariationId is 381210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.128 with no splicing effect.
• BS2: High AC in GnomAd4 at 1103 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.3411A>C	p.Pro1137Pro	synonymous	Exon 20 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.3411A>C	p.Pro1137Pro	synonymous	Exon 20 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.3411A>C	p.Pro1137Pro	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.3411A>C	p.Pro1137Pro	synonymous	Exon 20 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.3408A>C	p.Pro1136Pro	synonymous	Exon 20 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2603-5310A>C		intron	N/A	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.00725 AC: 1103 AN: 152156 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00723 AC: 1812 AN: 250788 AF XY: 0.00731

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00883

GnomAD4 exome AF: 0.0105 AC: 15338 AN: 1461736 Hom.: 95 Cov.: 35 AF XY: 0.0102 AC XY: 7399 AN XY: 727160

African (AFR) AF: 0.00149 AC: 50 AN: 33474

American (AMR) AF: 0.00230 AC: 103 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00224 AC: 193 AN: 86258

European-Finnish (FIN) AF: 0.0125 AC: 665 AN: 53324

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

European-Non Finnish (NFE) AF: 0.0124 AC: 13776 AN: 1111966

Other (OTH) AF: 0.00839 AC: 507 AN: 60394

GnomAD4 genome AF: 0.00724 AC: 1103 AN: 152274 Hom.: 8 Cov.: 31 AF XY: 0.00682 AC XY: 508 AN XY: 74466

African (AFR) AF: 0.00221 AC: 92 AN: 41576

American (AMR) AF: 0.00150 AC: 23 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.0114 AC: 121 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0123 AC: 837 AN: 68002

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00791 Hom.: 2

Bravo AF: 0.00638

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0108

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial acute necrotizing encephalopathy (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.8
DANN	Benign	0.41
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs76461420; hg19: chr2-109380406; COSMIC: COSV51702268;