rs587778822
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_181426.2(CCDC39):c.1072del(p.Thr358GlnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,539,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000079 ( 0 hom. )
Consequence
CCDC39
NM_181426.2 frameshift
NM_181426.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.409
Genes affected
CCDC39 (HGNC:25244): (coiled-coil domain 39 molecular ruler complex subunit) The protein encoded by this gene is involved in the motility of cilia and flagella. The encoded protein is essential for the assembly of dynein regulatory and inner dynein arm complexes, which regulate ciliary beat. Defects in this gene are a cause of primary ciliary dyskinesia type 14 (CILD14). [provided by RefSeq, Jul 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 3-180651495-GT-G is Pathogenic according to our data. Variant chr3-180651495-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 65998.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCDC39 | NM_181426.2 | c.1072del | p.Thr358GlnfsTer3 | frameshift_variant | 9/20 | ENST00000476379.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCDC39 | ENST00000476379.6 | c.1072del | p.Thr358GlnfsTer3 | frameshift_variant | 9/20 | 2 | NM_181426.2 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 151930Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000327 AC: 5AN: 153056Hom.: 0 AF XY: 0.0000374 AC XY: 3AN XY: 80256
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GnomAD4 exome AF: 0.00000793 AC: 11AN: 1387948Hom.: 0 Cov.: 28 AF XY: 0.0000102 AC XY: 7AN XY: 684662
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74340
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 14 Pathogenic:2
Pathogenic, no assertion criteria provided | curation | GeneReviews | Sep 15, 2011 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change creates a premature translational stop signal (p.Thr358Glnfs*3) in the CCDC39 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC39 are known to be pathogenic (PMID: 21131972, 23255504). This variant is present in population databases (rs587778822, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972, 22693285, 25186273). ClinVar contains an entry for this variant (Variation ID: 65998). 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at