rs139675596
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001384732.1(CPLANE1):c.7477C>T(p.Arg2493Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,610,252 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 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.7477C>T | p.Arg2493Ter | stop_gained | 36/53 | ENST00000651892.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPLANE1 | ENST00000651892.2 | c.7477C>T | p.Arg2493Ter | stop_gained | 36/53 | NM_001384732.1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000565 AC: 14AN: 247746Hom.: 0 AF XY: 0.0000822 AC XY: 11AN XY: 133790
GnomAD4 exome AF: 0.0000357 AC: 52AN: 1458174Hom.: 0 Cov.: 30 AF XY: 0.0000469 AC XY: 34AN XY: 725240
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74288
ClinVar
Submissions by phenotype
Joubert syndrome 17 Pathogenic:4Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 06, 2012 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 15, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 17 (MIM#614615) and Orofaciodigital syndrome 6 (MIM#277170). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0402 - Variant is located in a gene associated with a severe early-onset recessive condition that is intolerant to bi-allelic loss of function variants (gnomAD, OMIM). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple NMD-predicted variants have been reported as pathogenic or likely pathogenic in the ClinVar database. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in the compound heterozygous or homozygous state in multiple individuals with Joubert syndrome (ClinVar, PMID:22425360, 26092869, 25407461). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20W001158, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The homozygous p.Arg2493Ter variant in C5orf42 was identified by our study in one individual with Joubert syndrome. This variant has been identified in 0.005767% (14/242764) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139675596). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg2493Ter variant in C5orf42 has been reported as a causative variant in 3 mixed European and Native American families with Joubert syndrome and in the compound heterozygous state in one individual with a missense variant, which has been reported in trans with 3 other loss of function variants (PMID: 26092869, 22425360). Loss of function of the C5orf42 gene is an established disease mechanism for autosomal recessive Joubert syndrome, and this is a loss of function variant. In summary, the p.Arg2493Ter variant is pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_Supporting (Richards 2015). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2022 | Observed with a second CPLANE1 variant on the opposite allele (in trans) in an individual with Joubert syndrome in published literature (Srour et al., 2012); Observed with a second CPLANE1 variant or in the homozygous state in four individuals with Joubert syndrome from three unrelated families (Bachmann-Gagescu et al., 2015); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22425360, 26092869, 30712878) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 25, 2022 | This sequence change creates a premature translational stop signal (p.Arg2493*) 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 (rs139675596, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Joubert syndrome (PMID: 22425360, 26092869). ClinVar contains an entry for this variant (Variation ID: 31223). For these reasons, this variant has been classified as Pathogenic. - |
Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 29, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at