rs141153181
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong
The NM_001384732.1(CPLANE1):c.3599C>T(p.Ala1200Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1200E) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001384732.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPLANE1 | NM_001384732.1 | c.3599C>T | p.Ala1200Val | missense_variant | 20/53 | ENST00000651892.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPLANE1 | ENST00000651892.2 | c.3599C>T | p.Ala1200Val | missense_variant | 20/53 | NM_001384732.1 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152000Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251468Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135916
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727232
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152000Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74214
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1200 of the CPLANE1 protein (p.Ala1200Val). This variant is present in population databases (rs141153181, gnomAD 0.005%). This missense change has been observed in individual(s) with ciliopathy disorders (PMID: 24091540, 25407461, 27081551, 29605658). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217591). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CPLANE1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25846457, 27434533, 28431631, 25407461, 27081551, 29955609, 31965297, 29605658, 32047782, 35582950, 24091540, 26092869) - |
Orofaciodigital syndrome type 6 Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 14, 2024 | This variant is interpreted as pathogenic for Joubert syndrome with orofaciodigital defect (orofaciodigital syndrome 6). The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2_supporting). Cosegregation with disease in multiple affected family members (PP1_supporting; PMID: 29605658). For recessive disorders, detected in trans with a pathogenic variant (PM3_very strong; PMID: 25407461, 27081551, 29605658, 35582950, 24091540, 29955609). - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital | Feb 01, 2024 | - - |
Joubert syndrome 17 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at