chr3-180650140-T-C
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_181426.2(CCDC39):c.1167+1261A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 152,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)
Consequence
CCDC39
NM_181426.2 intron
NM_181426.2 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.13
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 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-180650140-T-C is Pathogenic according to our data. Variant chr3-180650140-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000467 AC: 71AN: 152178Hom.: 0 Cov.: 32
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We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome 0.000466 AC: 71AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74464
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Mar 07, 2018 | - - |
| Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Aug 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 24, 2024 | This sequence change falls in intron 9 of the CCDC39 gene. It does not directly change the encoded amino acid sequence of the CCDC39 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs577069249, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972; internal data). 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: 410378). Studies have shown that this variant results in activation of a pseudo-exon in intron 9, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 21131972). For these reasons, this variant has been classified as Pathogenic. - |
Primary ciliary dyskinesia 14 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2024 | Variant summary: CCDC39 c.1167+1261A>G is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00061 in 31404 control chromosomes. c.1167+1261A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Primary ciliary dyskinesia (e.g. Mani_2019, Davis_2019, Blanchon_2012, Alsamri_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34768622, 22693285, 30067075, 31469207). ClinVar contains an entry for this variant (Variation ID: 410378). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 12, 2024 | - - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2023 | Published functional studies demonstrate this variant results in activation of a pseudo-exon in intron 9 and is predicted to lead to p.(Glu390Serfs*6) (Merveille et al., 2011); This variant is associated with the following publications: (PMID: 21131972, 35051411, 31469207, 30067075, 22693285, 34768622) - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at