rs606231259
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001384732.1(CPLANE1):c.493del(p.Ile165TyrfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,551,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (โ โ ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: ๐ 0.000072 ( 0 hom., cov: 31)
Exomes ๐: 0.00018 ( 0 hom. )
Consequence
CPLANE1
NM_001384732.1 frameshift
NM_001384732.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.00400
Genes affected
CPLANE1 (HGNC:25801): (ciliogenesis and planar polarity effector complex subunit 1) The protein encoded by this gene has putative coiled-coil domains and may be a transmembrane protein. Defects in this gene are a cause of Joubert syndrome (JBTS). [provided by RefSeq, May 2012]
Genome browser will be placed here
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 5-37244451-AT-A is Pathogenic according to our data. Variant chr5-37244451-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 157513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37244451-AT-A is described in Lovd as [Pathogenic]. Variant chr5-37244451-AT-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPLANE1 | NM_001384732.1 | c.493del | p.Ile165TyrfsTer17 | frameshift_variant | 5/53 | ENST00000651892.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPLANE1 | ENST00000651892.2 | c.493del | p.Ile165TyrfsTer17 | frameshift_variant | 5/53 | NM_001384732.1 | A2 | ||
CPLANE1 | ENST00000508244.5 | c.493del | p.Ile165TyrfsTer17 | frameshift_variant | 4/51 | 5 | P2 | ||
CPLANE1 | ENST00000425232.7 | c.276del | p.Ile93TyrfsTer17 | frameshift_variant, NMD_transcript_variant | 2/30 | 5 | |||
CPLANE1 | ENST00000675547.1 | n.640+1027del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152050Hom.: 0 Cov.: 31
GnomAD3 genomes
?
AF:
AC:
11
AN:
152050
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000146 AC: 23AN: 157324Hom.: 0 AF XY: 0.000168 AC XY: 14AN XY: 83206
GnomAD3 exomes
AF:
AC:
23
AN:
157324
Hom.:
AF XY:
AC XY:
14
AN XY:
83206
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000181 AC: 253AN: 1399494Hom.: 0 Cov.: 31 AF XY: 0.000180 AC XY: 124AN XY: 690248
GnomAD4 exome
AF:
AC:
253
AN:
1399494
Hom.:
Cov.:
31
AF XY:
AC XY:
124
AN XY:
690248
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152168Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74392
GnomAD4 genome
?
AF:
AC:
11
AN:
152168
Hom.:
Cov.:
31
AF XY:
AC XY:
6
AN XY:
74392
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Joubert syndrome 17 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 12, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU Mรผnchen | Jan 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Aug 07, 2019 | This frameshifting variant in exon 5 of 52 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with Joubert syndrome (PMID: 25920555, 26092869, 28289185, 25407461, 29321670), as well as in individuals affected with Oral-Facial-Digital syndrome (PMID: 24178751). ClinVar contains an entry for this variant (Variation ID: 157513). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.013% (25/188678) and thus is presumed to be rare. Based on the available evidence, the c.493del (p.Ile165TyrfsTer17) variant is classified as Pathogenic. - |
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 | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with Joubert syndrome 17 (MIM#614615) and orofaciodigital syndrome VI (MIM#277170) (OMIM). (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 (25 heterozygotes, 0 homozygotes). (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 previously reported as pathogenic (ClinVar, Decipher) (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Joubert syndrome and Orofaciodigital syndrome (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics, University of Zurich | May 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Oct 27, 2020 | This CPLANE1 variant (rs968241708) is rare (<0.1%) in a large population dataset (25/188678 total alleles; 0.013%; no homozygotes) and has an entry in ClinVar. This variant has been reported previously in a compound heterozygous state in multiple unrelated individuals affected with JS or Oral-Facial-Digital syndrome (OFD). This frameshift variant results in a premature stop codon in exon 5 of 52 likely leading to nonsense-mediated decay and lack of protein production. We consider c.493delA to be pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 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: 25407461, 25920555, 29321670, 23523602, 24178751, 34426522, 26092869, 28289185) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Ile165Tyrfs*17) 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 (rs606231259, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome and oral-facial-digital syndrome (PMID: 24178751, 25920555, 26092869, 28289185). ClinVar contains an entry for this variant (Variation ID: 157513). 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 | Mar 24, 2022 | - - |
Orofaciodigital syndrome type 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 32
Find out detailed SpliceAI scores and Pangolin per-transcript scores at