chr2-108771695-T-G

Variant names:

• chr2-108771695-T-G
• rs183569993
• NM_006267.5:c.7850-6T>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The NM_006267.5(RANBP2):​c.7850-6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,611,682 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: RANBP2 NM_006267.5 splice_region, intron
• Scores: Splicing: ADA: 0.9852
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.01
• 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, 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 -11 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-108771695-T-G is Benign according to our data. Variant chr2-108771695-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 469490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 413 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.7850-6T>G		splice_region intron	N/A	NP_006258.3
	RANBP2	NM_001415871.1		c.7928-6T>G		splice_region intron	N/A	NP_001402800.1
	RANBP2	NM_001415873.1		c.7850-6T>G		splice_region intron	N/A	NP_001402802.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.7850-6T>G		splice_region intron	N/A	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.7847-6T>G		splice_region intron	N/A	ENSP00000588042.1
	RANBP2	ENST00000697745.1		c.2714-6T>G		splice_region intron	N/A	ENSP00000513429.1	A0A8V8TLN4

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00283 AC: 704 AN: 248354 AF XY: 0.00302

Gnomad AFR exome AF: 0.000567

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00613

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00343 AC: 5000 AN: 1459394 Hom.: 12 Cov.: 31 AF XY: 0.00346 AC XY: 2514 AN XY: 726090

African (AFR) AF: 0.000299 AC: 10 AN: 33470

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39660

South Asian (SAS) AF: 0.00398 AC: 343 AN: 86250

European-Finnish (FIN) AF: 0.00556 AC: 285 AN: 51244

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5762

European-Non Finnish (NFE) AF: 0.00372 AC: 4134 AN: 1111782

Other (OTH) AF: 0.00292 AC: 176 AN: 60376

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74474

African (AFR) AF: 0.000433 AC: 18 AN: 41562

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4828

European-Finnish (FIN) AF: 0.00800 AC: 85 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00401 AC: 273 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00387 Hom.: 1

Bravo AF: 0.00176

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00231

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.55
PhyloP100		1.0
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.76
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: rs183569993; hg19: chr2-109388151;