rs61748147

Variant names:

• chr2-108763494-G-A
• rs61748147
• NM_006267.5:c.2955G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006267.5(RANBP2):​c.2955G>A​(p.Pro985Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 1,614,010 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0072 (88 hom.)
• Consequence: RANBP2 NM_006267.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.290

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-108763494-G-A is Benign according to our data. Variant chr2-108763494-G-A is described in ClinVar as [Benign]. Clinvar id is 382463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-108763494-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00501 (763/152188) while in subpopulation SAS AF= 0.0212 (102/4814). AF 95% confidence interval is 0.0179. There are 4 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 763 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.2955G>A	p.Pro985Pro	synonymous_variant	Exon 20 of 29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.2955G>A	p.Pro985Pro	synonymous_variant	Exon 20 of 29	1	NM_006267.5	ENSP00000283195.6
RANBP2	ENST00000697737.1	c.2602+4946G>A		intron_variant	Intron 18 of 26			ENSP00000513426.1
RANBP2	ENST00000697740.1	c.2524+4946G>A		intron_variant	Intron 18 of 26			ENSP00000513427.1

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 762 AN: 152070 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00547

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00801 AC: 2010 AN: 251066 Hom.: 23 AF XY: 0.00828 AC XY: 1124 AN XY: 135682

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00466

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.0266

Gnomad SAS exome AF: 0.0200

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00537

Gnomad OTH exome AF: 0.00801

GnomAD4 exome AF: 0.00718 AC: 10493 AN: 1461822 Hom.: 88 Cov.: 34 AF XY: 0.00750 AC XY: 5457 AN XY: 727214

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.0346

Gnomad4 SAS exome AF: 0.0201

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00589

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.00501 AC: 763 AN: 152188 Hom.: 4 Cov.: 31 AF XY: 0.00535 AC XY: 398 AN XY: 74398

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.0201

Gnomad4 SAS AF: 0.0212

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00547

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00505 Hom.: 2

Bravo AF: 0.00504

Asia WGS AF: 0.0260 AC: 92 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial acute necrotizing encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.9
DANN	Benign	0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs61748147; hg19: chr2-109379950; COSMIC: COSV51696913;