12-130873046-C-T

Position:

• chr12-130873046-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_006325.5(RAN):​c.165C>T​(p.Asn55Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.00255 in 1,614,224 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (16 hom.)
• Consequence: RAN NM_006325.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.65

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]

RAN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-130873046-C-T is Benign according to our data. Variant chr12-130873046-C-T is described in ClinVar as [Benign]. Clinvar id is 713516.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 462 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAN	NM_006325.5	c.165C>T	p.Asn55Asn	synonymous_variant	4/7	ENST00000543796.6	NP_006316.1
RAN	NM_001300796.2	c.-100C>T		5_prime_UTR_variant	3/6		NP_001287725.1
RAN	NM_001300797.2	c.-100C>T		5_prime_UTR_variant	3/6		NP_001287726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAN	ENST00000543796.6	c.165C>T	p.Asn55Asn	synonymous_variant	4/7	1	NM_006325.5	ENSP00000446215.1
RAN	ENST00000541679.7	c.36+417C>T		intron_variant		5		ENSP00000483687.1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 462 AN: 152226 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0230

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00328 AC: 826 AN: 251490 Hom.: 3 AF XY: 0.00328 AC XY: 446 AN XY: 135920

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0240

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00250 AC: 3649 AN: 1461880 Hom.: 16 Cov.: 31 AF XY: 0.00246 AC XY: 1791 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.00204

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00303 AC: 462 AN: 152344 Hom.: 4 Cov.: 33 AF XY: 0.00377 AC XY: 281 AN XY: 74494

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.0230

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs145207608; hg19: chr12-131357591;