chr2-108765365-A-T

Variant names:

• chr2-108765365-A-T
• rs146669983
• NM_006267.5:c.4826A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006267.5(RANBP2):​c.4826A>T​(p.Gln1609Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000244 in 1,252,330 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.11
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016104579).
• BP6: Variant 2-108765365-A-T is Benign according to our data. Variant chr2-108765365-A-T is described in ClinVar as Benign. ClinVar VariationId is 469464.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 180 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.4826A>T	p.Gln1609Leu	missense	Exon 20 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.4826A>T	p.Gln1609Leu	missense	Exon 20 of 30	NP_001402800.1
	RANBP2	NM_001415873.1		c.4826A>T	p.Gln1609Leu	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.4826A>T	p.Gln1609Leu	missense	Exon 20 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.4823A>T	p.Gln1608Leu	missense	Exon 20 of 29	ENSP00000588042.1
	RANBP2	ENST00000960086.1		c.2603-3895A>T		intron	N/A	ENSP00000630145.1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 181 AN: 149870 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

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: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000322 AC: 80 AN: 248814 AF XY: 0.000193

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000114 AC: 126 AN: 1102342 Hom.: 1 Cov.: 26 AF XY: 0.0000924 AC XY: 52 AN XY: 563054

African (AFR) AF: 0.00405 AC: 109 AN: 26914

American (AMR) AF: 0.000181 AC: 8 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23922

East Asian (EAS) AF: 0.00 AC: 0 AN: 38170

South Asian (SAS) AF: 0.00 AC: 0 AN: 79084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.000393 AC: 2 AN: 5086

European-Non Finnish (NFE) AF: 0.00000255 AC: 2 AN: 783064

Other (OTH) AF: 0.000103 AC: 5 AN: 48542

GnomAD4 genome AF: 0.00120 AC: 180 AN: 149988 Hom.: 0 Cov.: 30 AF XY: 0.00116 AC XY: 85 AN XY: 73246

African (AFR) AF: 0.00435 AC: 177 AN: 40664

American (AMR) AF: 0.000133 AC: 2 AN: 15004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00 AC: 0 AN: 4634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67476

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.000471 Hom.: 0

ESP6500AA AF: 0.00552 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000395 AC: 48

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial acute necrotizing encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.028
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.1
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.012	B
Vest4		0.34
MVP		0.67
MPC		0.35
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.16
gMVP		0.49
Mutation Taster		=94/6	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: rs146669983; hg19: chr2-109381821;