chr2-224557750-T-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003590.5(CUL3):āc.173A>Gā(p.Tyr58Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 30)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CUL3
NM_003590.5 missense
NM_003590.5 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 7.86
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 Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 2-224557750-T-C is Pathogenic according to our data. Variant chr2-224557750-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CUL3 | NM_003590.5 | c.173A>G | p.Tyr58Cys | missense_variant | 2/16 | ENST00000264414.9 | NP_003581.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1458806Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725884
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1458806
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Cov.:
30
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AC XY:
0
AN XY:
725884
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 21, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2024 | Identified by exome sequencing in an individual with absent thumb, speech delays, failure to thrive, and microcephaly who also had other variants of uncertain significance in other genes (PMID: 30311385); Identified in a patient with an autism spectrum disorder; however, segregation information was not available (PMID: 31038196); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30311385, 31038196) - |
Autosomal dominant pseudohypoaldosteronism type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
NEURODEVELOPMENTAL DISORDER WITHOUT AUTISM OR SEIZURES Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 25, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Loss of phosphorylation at Y58 (P = 0.0823);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at