rs199810663
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2
The NM_001384732.1(CPLANE1):c.8958+4A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,610,100 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 10 hom. )
Consequence
CPLANE1
NM_001384732.1 splice_donor_region, intron
NM_001384732.1 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9927
2
Clinical Significance
Conservation
PhyloP100: 1.63
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
Variant 5-37125240-T-G is Benign according to our data. Variant chr5-37125240-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197551.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2, Benign=2}. Variant chr5-37125240-T-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00234 (357/152350) while in subpopulation AMR AF= 0.00314 (48/15296). AF 95% confidence interval is 0.00276. There are 2 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CPLANE1 | NM_001384732.1 | c.8958+4A>C | splice_donor_region_variant, intron_variant | ENST00000651892.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CPLANE1 | ENST00000651892.2 | c.8958+4A>C | splice_donor_region_variant, intron_variant | NM_001384732.1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00235 AC: 358AN: 152232Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.00260 AC: 645AN: 248302Hom.: 4 AF XY: 0.00257 AC XY: 345AN XY: 134304
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GnomAD4 exome AF: 0.00319 AC: 4656AN: 1457750Hom.: 10 Cov.: 31 AF XY: 0.00315 AC XY: 2287AN XY: 725030
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 15, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 13, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | CPLANE1: PP3, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 06, 2015 | - - |
Joubert syndrome 17 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
CPLANE1-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 24, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -16
Find out detailed SpliceAI scores and Pangolin per-transcript scores at