chr2-224557750-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_003590.5(CUL3):ā€‹c.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

Scores

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.86
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]

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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
CUL3NM_003590.5 linkc.173A>G p.Tyr58Cys missense_variant 2/16 ENST00000264414.9 NP_003581.1 Q13618-1A0A024R475

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CUL3ENST00000264414.9 linkc.173A>G p.Tyr58Cys missense_variant 2/161 NM_003590.5 ENSP00000264414.4 Q13618-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1458806
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
725884
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.00
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 submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 21, 2018- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 19, 2024Identified 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 submitterclinical testingMendelicsMay 28, 2019- -
NEURODEVELOPMENTAL DISORDER WITHOUT AUTISM OR SEIZURES Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 25, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;.;D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Uncertain
0.30
D
MutationAssessor
Pathogenic
3.5
M;.;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-8.5
D;D;D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.93
MutPred
0.92
Loss of phosphorylation at Y58 (P = 0.0823);.;.;
MVP
0.95
MPC
2.6
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs1553535841; hg19: chr2-225422467; API