chr3-180650140-T-C
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
Consequence
NM_181426.2 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000467 AC: 71AN: 152178Hom.: 0 Cov.: 32
GnomAD4 genome AF: 0.000466 AC: 71AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74464
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:3
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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
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. -
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not provided Pathogenic:1
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at