rs374144275
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001384732.1(CPLANE1):c.9220C>T(p.Arg3074Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000345 in 1,592,296 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
Consequence
NM_001384732.1 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPLANE1 | NM_001384732.1 | c.9220C>T | p.Arg3074Ter | stop_gained | 50/53 | ENST00000651892.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPLANE1 | ENST00000651892.2 | c.9220C>T | p.Arg3074Ter | stop_gained | 50/53 | NM_001384732.1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000306 AC: 7AN: 228766Hom.: 0 AF XY: 0.0000243 AC XY: 3AN XY: 123688
GnomAD4 exome AF: 0.0000188 AC: 27AN: 1439982Hom.: 0 Cov.: 28 AF XY: 0.00000978 AC XY: 7AN XY: 716006
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74492
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2022 | This sequence change creates a premature translational stop signal (p.Arg3020*) in the CPLANE1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPLANE1 are known to be pathogenic (PMID: 24178751, 26092869). This variant is present in population databases (rs374144275, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217569). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 27, 2021 | 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; This variant is associated with the following publications: (PMID: 26092869) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 10, 2022 | - - |
Joubert syndrome 17 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 25, 2020 | ACMG classification criteria: PVS1, PS4, PM2, PM3 - |
Joubert syndrome and related disorders Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 25, 2022 | Variant summary: CPLANE1 c.9058C>T (p.Arg3020X), also known as c.9220C>T (p.Arg3074X), results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.9376C>T [p.Gln3126Ter]; c.9339dup [p.Ala3114fs]). The variant allele was found at a frequency of 4.2e-05 in 260162 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CPLANE1 causing Joubert Syndrome And Related Disorders (4.2e-05 vs 0.0015), allowing no conclusion about variant significance. c.9058C>T has been reported in the literature as a biallelic genotype in at least one individual affected with Joubert Syndrome And Related Disorders (Bachmann-Gagescu_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all six classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.9058C>T;p.(Arg3020*) variant creates a premature translational stop signal in the CPLANE1 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 217569; PMID: 26092869) - PS4_moderate. The variant is present at low allele frequencies population databases (rs374144275 – gnomAD 0.0004228%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg3020*) was detected in trans with a pathogenic variant (PMID: 26092869) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at