2-224470492-A-G

Position:

• chr2-224470492-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003590.5(CUL3):​c.*3753T>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 0.00114 in 226,734 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00069 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.336

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-224470492-A-G is Benign according to our data. Variant chr2-224470492-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 334573.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000689 (102/147940) while in subpopulation SAS AF= 0.00111 (5/4524). AF 95% confidence interval is 0.000435. There are 2 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL3	NM_003590.5	c.*3753T>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.*3753T>C		3_prime_UTR_variant	16/16	1	NM_003590.5	ENSP00000264414	P1
	ENST00000620050.1	n.242-3489A>G		intron_variant, non_coding_transcript_variant		5
CUL3	ENST00000344951.8	c.*3753T>C		3_prime_UTR_variant	15/15	2		ENSP00000343601
	ENST00000622296.1	n.54-2435A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 102 AN: 147830 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000252

Gnomad OTH AF: 0.000490

GnomAD4 exome AF: 0.00199 AC: 157 AN: 78794 Hom.: 4 Cov.: 0 AF XY: 0.00224 AC XY: 81 AN XY: 36230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000412

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.000689 AC: 102 AN: 147940 Hom.: 2 Cov.: 33 AF XY: 0.000762 AC XY: 55 AN XY: 72190

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000253

Gnomad4 OTH AF: 0.000484

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000684

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pseudohypoaldosteronism type 2E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs558805673; hg19: chr2-225335209;