2-224470254-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003590.5(CUL3):c.*3991A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 218,334 control chromosomes in the GnomAD database, including 10,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (7139 hom., cov: 32)
  • Exomes 𝑓: 0.33 (3789 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.305

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-224470254-T-C is Benign according to our data. Variant chr2-224470254-T-C is described in ClinVar as [Benign]. Clinvar id is 334569.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL3	NM_003590.5	c.*3991A>G		3_prime_UTR_variant	16/16	ENST00000264414.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL3	ENST00000264414.9	c.*3991A>G		3_prime_UTR_variant	16/16	1	NM_003590.5	P1
	ENST00000620050.1	n.242-3727T>C		intron_variant, non_coding_transcript_variant		5
CUL3	ENST00000344951.8	c.*3991A>G		3_prime_UTR_variant	15/15	2
	ENST00000622296.1	n.53+2399T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45810 AN: 152030 Hom.: 7141 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.302

GnomAD4 exome AF: 0.333 AC: 22034 AN: 66186 Hom.: 3789 Cov.: 0 AF XY: 0.334 AC XY: 10239 AN XY: 30656

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.386

Gnomad4 EAS exome AF: 0.359

Gnomad4 SAS exome AF: 0.238

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.332

GnomAD4 genome AF: 0.301 AC: 45825 AN: 152148 Hom.: 7139 Cov.: 32 AF XY: 0.302 AC XY: 22460 AN XY: 74350

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.303

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.300

Alfa AF: 0.326 Hom.: 1689

Bravo AF: 0.303

Asia WGS AF: 0.319 AC: 1114 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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 13, 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	-0.83
Cadd	Benign	5.3
Dann	Benign	0.71

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: rs12470077; hg19: chr2-225334971;