2-108719562-C-T

Variant names:

• chr2-108719562-C-T
• rs79379002
• NM_006267.5:c.-45C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006267.5(RANBP2):​c.-45C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,578,448 control chromosomes in the GnomAD database, including 1,001 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (70 hom., cov: 32)
  • Exomes 𝑓: 0.035 (931 hom.)
• Consequence: RANBP2 NM_006267.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.60
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-108719562-C-T is Benign according to our data. Variant chr2-108719562-C-T is described in ClinVar as Benign. ClinVar VariationId is 380075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0229 (3487/152388) while in subpopulation NFE AF = 0.0364 (2473/68032). AF 95% confidence interval is 0.0352. There are 70 homozygotes in GnomAd4. There are 1591 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3487 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.-45C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 29	NP_006258.3
	RANBP2	NM_006267.5	MANE Select	c.-45C>T		5_prime_UTR	Exon 1 of 29	NP_006258.3
	RANBP2	NM_001415871.1		c.-45C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 30	NP_001402800.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.-45C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000283195.11	TSL:1 MANE Select	c.-45C>T		5_prime_UTR	Exon 1 of 29	ENSP00000283195.6	P49792
	RANBP2	ENST00000917983.1		c.-45C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 29	ENSP00000588042.1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3487 AN: 152270 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00750

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0351

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0256 AC: 4997 AN: 195412 AF XY: 0.0274

Gnomad AFR exome AF: 0.00604

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.000139

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0352 AC: 50143 AN: 1426060 Hom.: 931 Cov.: 30 AF XY: 0.0356 AC XY: 25172 AN XY: 706168

African (AFR) AF: 0.00513 AC: 169 AN: 32934

American (AMR) AF: 0.0111 AC: 431 AN: 38658

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 355 AN: 25380

East Asian (EAS) AF: 0.000131 AC: 5 AN: 38274

South Asian (SAS) AF: 0.0380 AC: 3104 AN: 81596

European-Finnish (FIN) AF: 0.0225 AC: 1126 AN: 50150

Middle Eastern (MID) AF: 0.0124 AC: 51 AN: 4102

European-Non Finnish (NFE) AF: 0.0394 AC: 43185 AN: 1095890

Other (OTH) AF: 0.0291 AC: 1717 AN: 59076

GnomAD4 genome AF: 0.0229 AC: 3487 AN: 152388 Hom.: 70 Cov.: 32 AF XY: 0.0213 AC XY: 1591 AN XY: 74522

African (AFR) AF: 0.00748 AC: 311 AN: 41604

American (AMR) AF: 0.0160 AC: 245 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5184

South Asian (SAS) AF: 0.0350 AC: 169 AN: 4834

European-Finnish (FIN) AF: 0.0175 AC: 186 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0364 AC: 2473 AN: 68032

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.0183 Hom.: 13

Bravo AF: 0.0220

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	10
DANN	Benign	0.78
PhyloP100		2.6
PromoterAI		-0.17	Neutral
Mutation Taster		=293/7	polymorphism (auto)

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: rs79379002; hg19: chr2-109336018;