2-224471097-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.*3148A>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 0.264 in 221,000 control chromosomes in the GnomAD database, including 8,660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5403 hom., cov: 33)
  • Exomes 𝑓: 0.30 (3257 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.491

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=-0.63).
• BP6: Variant 2-224471097-T-C is Benign according to our data. Variant chr2-224471097-T-C is described in ClinVar as [Benign]. Clinvar id is 334582.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.*3148A>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.*3148A>G		3_prime_UTR_variant	16/16	1	NM_003590.5	P1
	ENST00000620050.1	n.242-2884T>C		intron_variant, non_coding_transcript_variant		5
CUL3	ENST00000344951.8	c.*3148A>G		3_prime_UTR_variant	15/15	2
	ENST00000622296.1	n.54-1830T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37644 AN: 151964 Hom.: 5403 Cov.: 33

Gnomad AFR AF: 0.0916

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.302 AC: 20785 AN: 68918 Hom.: 3257 Cov.: 0 AF XY: 0.301 AC XY: 9580 AN XY: 31782

Gnomad4 AFR exome AF: 0.0933

Gnomad4 AMR exome AF: 0.315

Gnomad4 ASJ exome AF: 0.330

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.286

GnomAD4 genome AF: 0.248 AC: 37645 AN: 152082 Hom.: 5403 Cov.: 33 AF XY: 0.249 AC XY: 18500 AN XY: 74326

Gnomad4 AFR AF: 0.0915

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.258

Alfa AF: 0.293 Hom.: 2512

Bravo AF: 0.245

Asia WGS AF: 0.292 AC: 1017 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	-0.63
Cadd	Benign	8.1
Dann	Benign	0.82

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: rs17479770; hg19: chr2-225335814;