chr2-224470456-G-A

Variant names:

• chr2-224470456-G-A
• rs4234054
• NM_003590.5:c.*3789C>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.*3789C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 230,708 control chromosomes in the GnomAD database, including 114,034 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75304 hom., cov: 32)
  • Exomes 𝑓: 0.99 (38730 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.170

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]

ENSG00000274629 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-224470456-G-A is Benign according to our data. Variant chr2-224470456-G-A is described in ClinVar as [Benign]. Clinvar id is 334570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL3	NM_003590.5	c.*3789C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000264414.9	NP_003581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000264414	c.*3789C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_003590.5	ENSP00000264414.4
CUL3	ENST00000344951	c.*3789C>T		3_prime_UTR_variant	Exon 15 of 15	2		ENSP00000343601.4
ENSG00000274629	ENST00000620050.1	n.242-3525G>A		intron_variant	Intron 1 of 1	5
ENSG00000274629	ENST00000622296.1	n.54-2471G>A		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.994 AC: 151343 AN: 152206 Hom.: 75246 Cov.: 32

Gnomad AFR AF: 0.998

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 0.983

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.985

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.994

Gnomad OTH AF: 0.994

GnomAD4 exome AF: 0.994 AC: 77919 AN: 78384 Hom.: 38730 Cov.: 0 AF XY: 0.993 AC XY: 35803 AN XY: 36040

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.991

Gnomad4 ASJ exome AF: 0.983

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.994

Gnomad4 OTH exome AF: 0.994

GnomAD4 genome AF: 0.994 AC: 151460 AN: 152324 Hom.: 75304 Cov.: 32 AF XY: 0.994 AC XY: 74037 AN XY: 74486

Gnomad4 AFR AF: 0.998

Gnomad4 AMR AF: 0.992

Gnomad4 ASJ AF: 0.983

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 0.985

Gnomad4 NFE AF: 0.994

Gnomad4 OTH AF: 0.994

Alfa AF: 0.995 Hom.: 9496

Bravo AF: 0.995

Asia WGS AF: 0.999 AC: 3473 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pseudohypoaldosteronism type 2E Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.79
DANN	Benign	0.75

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: rs4234054; hg19: chr2-225335173;