chr3-180659576-TCTAA-T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_181426.2(CCDC39):c.610_613del(p.Leu204AsnfsTer27) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000011 in 1,459,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
CCDC39
NM_181426.2 frameshift, splice_region
NM_181426.2 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.20
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 20 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 3-180659576-TCTAA-T is Pathogenic according to our data. Variant chr3-180659576-TCTAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 525300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCDC39 | NM_181426.2 | c.610_613del | p.Leu204AsnfsTer27 | frameshift_variant, splice_region_variant | 6/20 | ENST00000476379.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCDC39 | ENST00000476379.6 | c.610_613del | p.Leu204AsnfsTer27 | frameshift_variant, splice_region_variant | 6/20 | 2 | NM_181426.2 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247388Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134070
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1459810Hom.: 0 AF XY: 0.0000138 AC XY: 10AN XY: 726024
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Leu204Asnfs*27) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with CCDC39-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 525300). 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. - |
Primary ciliary dyskinesia 14 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 28, 2022 | - - |
Computational scores
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Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at