rs770566897
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001329943.3(KIAA0586):c.704_705del(p.Gln235ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,226 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
KIAA0586
NM_001329943.3 frameshift
NM_001329943.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.46
Genes affected
KIAA0586 (HGNC:19960): (KIAA0586) This gene encodes a conserved centrosomal protein that functions in ciliogenesis and responds to hedgehog signaling. Mutations in this gene causes Joubert syndrome 23. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 14-58444071-CAA-C is Pathogenic according to our data. Variant chr14-58444071-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 204596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-58444071-CAA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KIAA0586 | NM_001329943.3 | c.704_705del | p.Gln235ArgfsTer7 | frameshift_variant | 6/31 | ENST00000652326.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KIAA0586 | ENST00000652326.2 | c.704_705del | p.Gln235ArgfsTer7 | frameshift_variant | 6/31 | NM_001329943.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152132Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000282 AC: 7AN: 248662Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134868
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GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461094Hom.: 0 AF XY: 0.0000261 AC XY: 19AN XY: 726816
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2022 | Frameshift 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; This variant is associated with the following publications: (PMID: 34611884, 26096313, 32581362, 26026149) - |
Joubert syndrome 23 Pathogenic:2
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Sep 01, 2015 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 11, 2015 | - - |
Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jun 28, 2021 | - - |
Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 204596). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26096313). This variant is present in population databases (rs770566897, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Gln288Argfs*7) in the KIAA0586 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIAA0586 are known to be pathogenic (PMID: 26096313, 26166481, 26386044). - |
Intellectual disability;C4551714:Rod-cone dystrophy;C5231391:Congenital cerebellar hypoplasia Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Computational scores
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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