2-224470782-A-G

Position:

chr2-224470782-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.573

Variant links:

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]

CUL3 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 899 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL3	NM_003590.5 linkuse as main transcript	c.*3463T>C		3_prime_UTR_variant	16/16	ENST00000264414.9	NP_003581.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000264414.9 linkuse as main transcript	c.*3463T>C	3_prime_UTR_variant	16/16	1	NM_003590.5	ENSP00000264414	P1	Q13618-1
	ENST00000620050.1 linkuse as main transcript	n.242-3199A>G	intron_variant, non_coding_transcript_variant		5
CUL3	ENST00000344951.8 linkuse as main transcript	c.*3463T>C	3_prime_UTR_variant	15/15	2		ENSP00000343601		Q13618-3
	ENST00000622296.1 linkuse as main transcript	n.54-2145A>G	intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00590

AC:

898

AN:

152250

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

36504

show subpopulations

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.:

Cov.:

AF XY:

0.00540

AC XY:

402

AN XY:

74506

show subpopulations

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.:

Bravo

AF:

0.00683

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over