2-224471300-C-G
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_003590.5(CUL3):c.*2945G>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 0.00441 in 204,628 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0042 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0051 ( 1 hom. )
Consequence
CUL3
NM_003590.5 3_prime_UTR
NM_003590.5 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0330
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 2-224471300-C-G is Benign according to our data. Variant chr2-224471300-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 334586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00418 (636/152176) while in subpopulation NFE AF= 0.00677 (460/67982). AF 95% confidence interval is 0.00626. There are 2 homozygotes in gnomad4. There are 308 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 636 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CUL3 | NM_003590.5 | c.*2945G>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.*2945G>C | 3_prime_UTR_variant | 16/16 | 1 | NM_003590.5 | ENSP00000264414 | P1 | ||
ENST00000620050.1 | n.242-2681C>G | intron_variant, non_coding_transcript_variant | 5 | |||||||
CUL3 | ENST00000344951.8 | c.*2945G>C | 3_prime_UTR_variant | 15/15 | 2 | ENSP00000343601 | ||||
ENST00000622296.1 | n.54-1627C>G | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00419 AC: 637AN: 152058Hom.: 2 Cov.: 33
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GnomAD4 exome AF: 0.00509 AC: 267AN: 52452Hom.: 1 Cov.: 0 AF XY: 0.00510 AC XY: 124AN XY: 24306
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GnomAD4 genome AF: 0.00418 AC: 636AN: 152176Hom.: 2 Cov.: 33 AF XY: 0.00414 AC XY: 308AN XY: 74414
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
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 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | CUL3: BS1, BS2 - |
Pseudohypoaldosteronism type 2E Benign:1
Benign, 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 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
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at