2-224470878-A-G

Position:

• chr2-224470878-A-G

Variant summary

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

The ENST00000264414.9(CUL3):​c.*3367T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 229,088 control chromosomes in the GnomAD database, including 28,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18671 hom., cov: 33)
  • Exomes 𝑓: 0.51 (10122 hom.)
• Consequence: CUL3 ENST00000264414.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.980

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-224470878-A-G is Benign according to our data. Variant chr2-224470878-A-G is described in ClinVar as [Benign]. Clinvar id is 334580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL3	NM_003590.5	c.*3367T>C		3_prime_UTR_variant	16/16	ENST00000264414.9	NP_003581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000264414.9	c.*3367T>C		3_prime_UTR_variant	16/16	1	NM_003590.5	ENSP00000264414	P1
	ENST00000620050.1	n.242-3103A>G		intron_variant, non_coding_transcript_variant		5
CUL3	ENST00000344951.8	c.*3367T>C		3_prime_UTR_variant	15/15	2		ENSP00000343601
	ENST00000622296.1	n.54-2049A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74831 AN: 151916 Hom.: 18647 Cov.: 33

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.491

GnomAD4 exome AF: 0.507 AC: 39067 AN: 77054 Hom.: 10122 Cov.: 0 AF XY: 0.507 AC XY: 18037 AN XY: 35560

Gnomad4 AFR exome AF: 0.470

Gnomad4 AMR exome AF: 0.572

Gnomad4 ASJ exome AF: 0.517

Gnomad4 EAS exome AF: 0.662

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.268

Gnomad4 NFE exome AF: 0.472

Gnomad4 OTH exome AF: 0.498

GnomAD4 genome AF: 0.493 AC: 74897 AN: 152034 Hom.: 18671 Cov.: 33 AF XY: 0.497 AC XY: 36921 AN XY: 74310

Gnomad4 AFR AF: 0.482

Gnomad4 AMR AF: 0.575

Gnomad4 ASJ AF: 0.497

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.486

Alfa AF: 0.486 Hom.: 25164

Bravo AF: 0.501

Asia WGS AF: 0.599 AC: 2083 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.87
CADD	Benign	0.12
DANN	Benign	0.46

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: rs4674908; hg19: chr2-225335595;