rs141507441
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001384732.1(CPLANE1):c.8872C>T(p.Arg2958Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,420 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R2958R) has been classified as Likely benign. 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.8872C>T | p.Arg2958Ter | stop_gained | 47/53 | ENST00000651892.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPLANE1 | ENST00000651892.2 | c.8872C>T | p.Arg2958Ter | stop_gained | 47/53 | NM_001384732.1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151874Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251214Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135778
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461546Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727072
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 151874Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74142
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg2904*) 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 (rs141507441, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 25920555, 26092869). ClinVar contains an entry for this variant (Variation ID: 217571). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 14, 2022 | 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: 30408610, 31130284, 32233090, 25920555) - |
Pathogenic, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | May 01, 2022 | DNA sequence analysis of the CPLANE1 gene demonstrated a sequence change, c.8710C>T, in exon 46 that results in the creation of a premature stop codon at amino acid position 2904, p.Arg2904*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CPLANE1 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.0057% in the Latino/Admixed American subpopulation (dbSNP rs141507441). This pathogenic sequence change has previously been described in several individuals with CPLANE1-related disorders in the homozygous or compound heterozygous state (PMID: 25920555, 32233090). Pathogenic variants in CPLANE1 are associated with autosomal recessive Joubert syndrome and autosomal recessive Orofaciodigital syndrome VI [OMIM# 614571]. The CPLANE1 cDNA reference sequence used is NM_023073.3. - |
Joubert syndrome 17 Pathogenic:2Other:1
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 | May 06, 2021 | 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 <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least nine pathogenic NMD-predicted variants that have been previously reported (ClinVar, Decipher, PMID: 29605658) (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in five individuals diagnosed with Joubert syndrome or skeletal dysplasia (ClinVar, PMIDs: 25920555; 30408610; 32233090). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_023073.3 (CPLANE1): c.2932C>T; p.A(rg978*)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2021 | The c.8710C>T (p.R2904*) alteration, located in exon 46 (coding exon 45) of the C5orf42 gene, consists of a C to T substitution at nucleotide position 8710. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 2904. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation has been reported in the homozygous or compound heterozygous state in several individuals with a diagnosis of CPLANE1-related ciliopathy (Kroes, 2016; Monies, 2019; Liu, 2020). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at