2-108719625-G-A

Position:

• chr2-108719625-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006267.5(RANBP2):​c.19G>A​(p.Asp7Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23051336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.19G>A	p.Asp7Asn	missense_variant	1/29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.19G>A	p.Asp7Asn	missense_variant	1/29	1	NM_006267.5	ENSP00000283195.6
RANBP2	ENST00000697737.1	c.19G>A	p.Asp7Asn	missense_variant	1/27			ENSP00000513426.1
RANBP2	ENST00000425282.4	n.19G>A		non_coding_transcript_exon_variant	1/4	5		ENSP00000398970.2
RANBP2	ENST00000697738.1	n.128G>A		non_coding_transcript_exon_variant	1/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455338 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.19G>A (p.D7N) alteration is located in exon 1 (coding exon 1) of the RANBP2 gene. This alteration results from a G to A substitution at nucleotide position 19, causing the aspartic acid (D) at amino acid position 7 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.094
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.46	P;.
Vest4		0.29
MutPred		0.16		Gain of methylation at K5 (P = 0.0559);Gain of methylation at K5 (P = 0.0559);
MVP		0.34
MPC		0.47
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.40
gMVP		0.39

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: rs1694043828; hg19: chr2-109336081;