rs7958223

Variant names:

• chr12-130874753-C-A
• rs7958223
• NM_006325.5:c.435+20C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-130874753-C-A
• chr12-130874753-C-G
• chr12-130874753-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006325.5(RAN):​c.435+20C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,585,404 control chromosomes in the GnomAD database, including 72,135 homozygotes. 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: 𝑓 0.31 (7355 hom., cov: 33)
  • Exomes 𝑓: 0.30 (64780 hom.)
• Consequence: RAN NM_006325.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.17

Genes affected

RAN (HGNC:9846): (RAN, member RAS oncogene family) RAN (ras-related nuclear protein) is a small GTP binding protein belonging to the RAS superfamily that is essential for the translocation of RNA and proteins through the nuclear pore complex. The RAN protein is also involved in control of DNA synthesis and cell cycle progression. Nuclear localization of RAN requires the presence of regulator of chromosome condensation 1 (RCC1). Mutations in RAN disrupt DNA synthesis. Because of its many functions, it is likely that RAN interacts with several other proteins. RAN regulates formation and organization of the microtubule network independently of its role in the nucleus-cytosol exchange of macromolecules. RAN could be a key signaling molecule regulating microtubule polymerization during mitosis. RCC1 generates a high local concentration of RAN-GTP around chromatin which, in turn, induces the local nucleation of microtubules. RAN is an androgen receptor (AR) coactivator that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to Kennedy's disease (X-linked spinal and bulbar muscular atrophy). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of Kennedy's disease. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAN	NM_006325.5	c.435+20C>A		intron_variant	Intron 5 of 6	ENST00000543796.6	NP_006316.1
RAN	NM_001300796.2	c.171+20C>A		intron_variant	Intron 4 of 5		NP_001287725.1
RAN	NM_001300797.2	c.171+20C>A		intron_variant	Intron 4 of 5		NP_001287726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAN	ENST00000543796.6	c.435+20C>A		intron_variant	Intron 5 of 6	1	NM_006325.5	ENSP00000446215.1
RAN	ENST00000541679.7	c.37-902C>A		intron_variant	Intron 2 of 3	5		ENSP00000483687.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47421 AN: 151946 Hom.: 7347 Cov.: 33

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.302

GnomAD2 exomes AF: 0.298 AC: 72742 AN: 244406 AF XY: 0.294

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.299 AC: 428326 AN: 1433338 Hom.: 64780 Cov.: 27 AF XY: 0.296 AC XY: 211158 AN XY: 713126

Gnomad4 AFR exome AF: 0.318 AC: 10411 AN: 32732

Gnomad4 AMR exome AF: 0.299 AC: 12959 AN: 43340

Gnomad4 ASJ exome AF: 0.339 AC: 8693 AN: 25614

Gnomad4 EAS exome AF: 0.247 AC: 9727 AN: 39442

Gnomad4 SAS exome AF: 0.202 AC: 17049 AN: 84432

Gnomad4 FIN exome AF: 0.364 AC: 19397 AN: 53216

Gnomad4 NFE exome AF: 0.304 AC: 331218 AN: 1089522

Gnomad4 Remaining exome AF: 0.293 AC: 17371 AN: 59378

GnomAD4 genome AF: 0.312 AC: 47449 AN: 152066 Hom.: 7355 Cov.: 33 AF XY: 0.312 AC XY: 23208 AN XY: 74334

Gnomad4 AFR AF: 0.320 AC: 0.320257 AN: 0.320257

Gnomad4 AMR AF: 0.307 AC: 0.307405 AN: 0.307405

Gnomad4 ASJ AF: 0.329 AC: 0.329107 AN: 0.329107

Gnomad4 EAS AF: 0.213 AC: 0.213457 AN: 0.213457

Gnomad4 SAS AF: 0.194 AC: 0.193844 AN: 0.193844

Gnomad4 FIN AF: 0.390 AC: 0.390108 AN: 0.390108

Gnomad4 NFE AF: 0.311 AC: 0.311423 AN: 0.311423

Gnomad4 OTH AF: 0.301 AC: 0.30104 AN: 0.30104

Alfa AF: 0.260 Hom.: 1214

Bravo AF: 0.306

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0040
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs7958223; hg19: chr12-131359298; COSMIC: COSV54562340; COSMIC: COSV54562340;