rs397515392
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_181426.2(CCDC39):c.357+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000141 in 1,577,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_181426.2 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 151920Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000155 AC: 31AN: 199632Hom.: 0 AF XY: 0.000197 AC XY: 21AN XY: 106402
GnomAD4 exome AF: 0.000149 AC: 212AN: 1425102Hom.: 0 Cov.: 30 AF XY: 0.000153 AC XY: 108AN XY: 705476
GnomAD4 genome AF: 0.0000658 AC: 10AN: 151920Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5AN XY: 74198
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 14 Pathogenic:5
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ACMG classification criteria: PVS1 strong, PM3 strong -
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Primary ciliary dyskinesia Pathogenic:2
The c.357+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the CCDC39 gene. This alteration was detected in the homozygous state, and in conjunction with another alteration in CCDC39, in multiple individuals with CCDC39-related primary ciliary dyskinesia ((Merveille AC et al. Nat Genet, 2011 Jan;43:72-8; Antony D et al. Hum Mutat, 2013 Mar;34:462-72; Blanchon S et al. J Med Genet, 2020 Apr;57:237-244; Baz-Redón N et al. Arch Bronconeumol (Engl Ed), 2021 Mar;57:186-194). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
This sequence change affects a donor splice site in intron 3 of the CCDC39 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CCDC39 are known to be pathogenic (PMID: 21131972, 23255504). This variant is present in population databases (rs397515392, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972, 22693295, 23255504). 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: 31067). 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. -
not provided Pathogenic:2
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23255504, 22693295, 30067075, 22693285, 32253119, 31589614, 25525159, 20301301, 33988008, 31772028, 21131972) -
CCDC39: PM3:Very Strong, PM2, PVS1:Moderate -
Infertility disorder Pathogenic:1
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CCDC39-related disorder Pathogenic:1
The CCDC39 c.357+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with primary ciliary dyskinesia (Merveille et al. 2011. PubMed ID: 21131972; Blanchon et al. 2019. PubMed ID: 31772028; Baz-Redón et al. 2020. PubMed ID: 32253119). This variant is reported in 0.038% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in CCDC39 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at