chr2-108767148-G-A

Position:

• chr2-108767148-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006267.5(RANBP2):​c.6609G>A​(p.Ala2203Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00838 in 1,611,648 control chromosomes in the GnomAD database, including 695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (411 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (284 hom.)
• Consequence: RANBP2 NM_006267.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.734

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=-0.89).
• BP6: Variant 2-108767148-G-A is Benign according to our data. Variant chr2-108767148-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 380106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.734 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.6609G>A	p.Ala2203Ala	synonymous_variant	20/29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.6609G>A	p.Ala2203Ala	synonymous_variant	20/29	1	NM_006267.5	ENSP00000283195.6

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6318 AN: 151978 Hom.: 410 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0114 AC: 2804 AN: 247028 Hom.: 156 AF XY: 0.00893 AC XY: 1200 AN XY: 134370

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00492 AC: 7175 AN: 1459552 Hom.: 284 Cov.: 33 AF XY: 0.00436 AC XY: 3169 AN XY: 726108

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.00540

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000765

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0416 AC: 6332 AN: 152096 Hom.: 411 Cov.: 32 AF XY: 0.0399 AC XY: 2971 AN XY: 74374

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0210

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0268 Hom.: 36

Bravo AF: 0.0485

EpiCase AF: 0.00142

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial acute necrotizing encephalopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 05, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 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. -

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	-0.89
CADD	Benign	0.63
DANN	Benign	0.47

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: rs60199637; hg19: chr2-109383604;