rs773662834
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_001384732.1(CPLANE1):c.7588+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,604,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001384732.1 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CPLANE1 | NM_001384732.1 | c.7588+7A>G | splice_region_variant, intron_variant | ENST00000651892.2 | NP_001371661.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CPLANE1 | ENST00000651892.2 | c.7588+7A>G | splice_region_variant, intron_variant | NM_001384732.1 | ENSP00000498265 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251190Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135770
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1452890Hom.: 0 Cov.: 28 AF XY: 0.0000124 AC XY: 9AN XY: 723506
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 09, 2022 | This sequence change falls in intron 37 of the CPLANE1 gene. It does not directly change the encoded amino acid sequence of the CPLANE1 protein. This variant is present in population databases (rs773662834, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of Joubert syndrome and related disorders (PMID: 28431631; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 582245). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2022 | Identified with a second variant in a patient with Joubert syndrome in the published literature (Enokizono et al., 2017); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28431631) - |
Orofaciodigital syndrome type 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Joubert syndrome and related disorders Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 31, 2024 | Variant summary: CPLANE1 c.7588+7A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 37 and truncation of protein leading to potential nonsense-mediated decay (Martnez-Rubio_2023). The variant was absent in 251190 control chromosomes. c.7588+7A>G has been reported in the literature as compound heterozygous genotype in individuals affected with Joubert Syndrome And Related Disorders (Enokizono_2017, Sakamoto_2022, Martnez-Rubio_2023). These data suggesting that the variant is probably associated disease. The following publications have been ascertained in the context of this evaluation (PMID: 28431631, 36305856, 38003592). ClinVar contains an entry for this variant (Variation ID: 582245). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at