rs3754629

Positions:

• chr2-224502952-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003590.5(CUL3):​c.1485+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,578,040 control chromosomes in the GnomAD database, including 21,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2951 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18208 hom.)
• Consequence: CUL3 NM_003590.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.817

Genes affected

CUL3 (HGNC:2553): (cullin 3) This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation. Mutations in this gene are a cause of type 2E pseudohypoaldosteronism. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-224502952-C-T is Benign according to our data. Variant chr2-224502952-C-T is described in ClinVar as [Benign]. Clinvar id is 259090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL3	NM_003590.5	c.1485+13G>A		intron_variant		ENST00000264414.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL3	ENST00000264414.9	c.1485+13G>A		intron_variant		1	NM_003590.5	P1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28180 AN: 151936 Hom.: 2940 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.185 AC: 46189 AN: 249288 Hom.: 4919 AF XY: 0.184 AC XY: 24715 AN XY: 134640

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.271

Gnomad SAS exome AF: 0.262

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.151 AC: 215250 AN: 1425988 Hom.: 18208 Cov.: 26 AF XY: 0.153 AC XY: 109003 AN XY: 711402

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.290

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.186 AC: 28224 AN: 152052 Hom.: 2951 Cov.: 32 AF XY: 0.189 AC XY: 14072 AN XY: 74324

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.183

Alfa AF: 0.150 Hom.: 354

Bravo AF: 0.191

Asia WGS AF: 0.274 AC: 952 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pseudohypoaldosteronism type 2E Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3754629; hg19: chr2-225367669; COSMIC: COSV52365070; COSMIC: COSV52365070;