rs202058504
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018451.5(CENPJ):c.1586C>G(p.Ser529*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000092 ( 0 hom. )
Consequence
CENPJ
NM_018451.5 stop_gained
NM_018451.5 stop_gained
Scores
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Clinical Significance
Conservation
PhyloP100: 0.156
Genes affected
CENPJ (HGNC:17272): (centromere protein J) This gene encodes a protein that belongs to the centromere protein family. During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. This protein can function as a transcriptional coactivator in the Stat5 signaling pathway, and also as a coactivator of NF-kappaB-mediated transcription, likely via its interaction with the coactivator p300/CREB-binding protein. Mutations in this gene are associated with primary autosomal recessive microcephaly, a disorder characterized by severely reduced brain size and cognitive disability. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-24906452-G-C is Pathogenic according to our data. Variant chr13-24906452-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 158194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CENPJ | ENST00000381884.9 | c.1586C>G | p.Ser529* | stop_gained | 7/17 | 1 | NM_018451.5 | ENSP00000371308.4 | ||
| CENPJ | ENST00000616936.4 | n.1586C>G | non_coding_transcript_exon_variant | 7/16 | 1 | ENSP00000477511.1 | ||||
| CENPJ | ENST00000545981.6 | n.1586C>G | non_coding_transcript_exon_variant | 7/18 | 2 | ENSP00000441090.2 |
Frequencies
GnomAD3 genomes 0.0000985 AC: 15AN: 152226Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000956 AC: 24AN: 250986Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135718
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GnomAD4 exome AF: 0.0000923 AC: 135AN: 1461850Hom.: 0 Cov.: 34 AF XY: 0.0000880 AC XY: 64AN XY: 727222
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GnomAD4 genome 0.0000985 AC: 15AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74360
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly 6, primary, autosomal recessive Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Nov 03, 2022 | The c.1586C>G;p.(Ser529*) variant creates a premature translational stop signal in the CENPJ gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (Clinvar ID: 158194) - PS4_supporting. The variant is present at low allele frequencies population databases (rs202058504 – gnomAD 0.001169%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology | - | A previously undescribed nucleotide variant creates a premature translation stop signal p.Ser529Ter in the CENPJ gene. The variant was observed in presumably compound heterozygous state with another LoF variant (phase not tested) in an individual affected with microcephaly and micrognathia. Homozygous and compound heterozygous variants are reported in patients with Microcephaly 6, primary, autosomal recessive, 608393, and Seckel syndrome 4, 613676. The variant is present in gnomAD population database at low frequency (24/250986 chromosomes, no homozygotes). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic. - |
not provided Pathogenic:1Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Ser529*) in the CENPJ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CENPJ are known to be pathogenic (PMID: 15793586, 16900296, 20522431). This variant is present in population databases (rs202058504, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CENPJ-related conditions. ClinVar contains an entry for this variant (Variation ID: 158194). For these reasons, this variant has been classified as Pathogenic. - |
| Uncertain significance, flagged submission | clinical testing | GeneDx | Jun 08, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614) - |
Microcephaly 6, primary, autosomal recessive;C3888212:Seckel syndrome 4 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at