chr2-108729187-A-C

Variant names:

• chr2-108729187-A-C
• rs751086162
• NM_006267.5:c.128A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006267.5(RANBP2):​c.128A>C​(p.Asp43Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.20

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39287508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP2	NM_006267.5	c.128A>C	p.Asp43Ala	missense_variant	Exon 2 of 29	ENST00000283195.11	NP_006258.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RANBP2	ENST00000283195.11	c.128A>C	p.Asp43Ala	missense_variant	Exon 2 of 29	1	NM_006267.5	ENSP00000283195.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000446 AC: 1 AN: 224442 Hom.: 0 AF XY: 0.00000817 AC XY: 1 AN XY: 122442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000567

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.06e-7 AC: 1 AN: 1417412 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 705104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

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

Bravo AF: 0.00000378

ExAC AF: 0.00000843 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Benign	0.27
Sift	Uncertain	0.015	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.89	P;.
Vest4		0.61
MutPred		0.20		Loss of ubiquitination at K47 (P = 0.052);Loss of ubiquitination at K47 (P = 0.052);
MVP		0.44
MPC		0.52
ClinPred		0.66	D
GERP RS		4.3
Varity_R		0.50
gMVP		0.35

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: rs751086162; hg19: chr2-109345643;