2-224470782-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003590.5(CUL3):c.*3463T>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 0.00434 in 231,746 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.573

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=-0.89).
• BP6: Variant 2-224470782-A-G is Benign according to our data. Variant chr2-224470782-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 334578.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0059 (899/152368) while in subpopulation AFR AF= 0.0204 (847/41588). AF 95% confidence interval is 0.0192. There are 12 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 898 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL3	NM_003590.5	c.*3463T>C		3_prime_UTR_variant	16/16	ENST00000264414.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL3	ENST00000264414.9	c.*3463T>C		3_prime_UTR_variant	16/16	1	NM_003590.5	P1
	ENST00000620050.1	n.242-3199A>G		intron_variant, non_coding_transcript_variant		5
CUL3	ENST00000344951.8	c.*3463T>C		3_prime_UTR_variant	15/15	2
	ENST00000622296.1	n.54-2145A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 898 AN: 152250 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00135 AC: 107 AN: 79378 Hom.: 1 Cov.: 0 AF XY: 0.00123 AC XY: 45 AN XY: 36504

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000305

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00590 AC: 899 AN: 152368 Hom.: 12 Cov.: 33 AF XY: 0.00540 AC XY: 402 AN XY: 74506

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000592 Hom.: 0

Bravo AF: 0.00683

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Likely 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	-0.89
Cadd	Benign	2.3
Dann	Benign	0.49

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: rs76433087; hg19: chr2-225335499;