chr13-24884443-A-ATTC
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_018451.5(CENPJ):c.3497_3498insGAA(p.Lys1165dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000090 ( 0 hom. )
Consequence
CENPJ
NM_018451.5 inframe_insertion
NM_018451.5 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.45
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_018451.5. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 13-24884443-A-ATTC is Pathogenic according to our data. Variant chr13-24884443-A-ATTC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210667.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CENPJ | NM_018451.5 | c.3497_3498insGAA | p.Lys1165dup | inframe_insertion | 14/17 | ENST00000381884.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CENPJ | ENST00000381884.9 | c.3497_3498insGAA | p.Lys1165dup | inframe_insertion | 14/17 | 1 | NM_018451.5 | P1 | |
CENPJ | ENST00000616936.4 | c.*151_*152insGAA | 3_prime_UTR_variant, NMD_transcript_variant | 13/16 | 1 | ||||
CENPJ | ENST00000471870.1 | n.387_388insGAA | non_coding_transcript_exon_variant | 5/5 | 3 | ||||
CENPJ | ENST00000545981.6 | c.*237_*238insGAA | 3_prime_UTR_variant, NMD_transcript_variant | 15/18 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251224Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135818
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GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461820Hom.: 0 Cov.: 36 AF XY: 0.0000784 AC XY: 57AN XY: 727216
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Seckel syndrome 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 26, 2014 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 13, 2022 | This variant, c.3495_3497dup, results in the insertion of 1 amino acid(s) of the CENPJ protein (p.Lys1165dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776528706, gnomAD 0.006%). 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: 210667). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at