2-108768293-T-C

Variant names:

• chr2-108768293-T-C
• rs145886643
• NM_006267.5:c.7754T>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.7754T>C​(p.Ile2585Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,612,030 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2585V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (42 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.59
• Publications: 7 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 (MetaRNN=0.0031910837).
• BP6: Variant 2-108768293-T-C is Benign according to our data. Variant chr2-108768293-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 728 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.7754T>C	p.Ile2585Thr	missense	Exon 20 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.7754T>C	p.Ile2585Thr	missense	Exon 20 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.7754T>C	p.Ile2585Thr	missense	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.7754T>C	p.Ile2585Thr	missense	Exon 20 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.7751T>C	p.Ile2584Thr	missense	Exon 20 of 29	ENSP00000588042.1
	RANBP2	ENST00000697745.1		c.2618T>C	p.Ile873Thr	missense	Exon 1 of 10	ENSP00000513429.1	A0A8V8TLN4

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 728 AN: 152222 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00453 AC: 1128 AN: 248980 AF XY: 0.00454

Gnomad AFR exome AF: 0.000992

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.00693

GnomAD4 exome AF: 0.00622 AC: 9080 AN: 1459690 Hom.: 42 Cov.: 33 AF XY: 0.00609 AC XY: 4423 AN XY: 726150

African (AFR) AF: 0.000898 AC: 30 AN: 33406

American (AMR) AF: 0.00718 AC: 321 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86162

European-Finnish (FIN) AF: 0.00118 AC: 63 AN: 53420

Middle Eastern (MID) AF: 0.00774 AC: 32 AN: 4136

European-Non Finnish (NFE) AF: 0.00740 AC: 8230 AN: 1111826

Other (OTH) AF: 0.00550 AC: 331 AN: 60206

GnomAD4 genome AF: 0.00478 AC: 728 AN: 152340 Hom.: 5 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74494

African (AFR) AF: 0.00139 AC: 58 AN: 41578

American (AMR) AF: 0.0102 AC: 156 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00695 AC: 473 AN: 68030

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00122 Hom.: 1

Bravo AF: 0.00544

ESP6500AA AF: 0.00183 AC: 8

ESP6500EA AF: 0.00643 AC: 55

ExAC AF: 0.00443 AC: 537

EpiCase AF: 0.00720

EpiControl AF: 0.00824

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Familial acute necrotizing encephalopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0020
DANN	Benign	0.22
DEOGEN2	Benign	0.14	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L
PhyloP100		-3.6
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.054
Sift	Benign	0.68	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.039
MVP		0.14
MPC		0.44
ClinPred		0.00074	T
GERP RS		-10
Varity_R		0.015
gMVP		0.14
Mutation Taster		=99/1	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: rs145886643; hg19: chr2-109384749;