rs756235547
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_181426.2(CCDC39):c.610-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,610,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_181426.2 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCDC39 | NM_181426.2 | c.610-2A>G | splice_acceptor_variant | ENST00000476379.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCDC39 | ENST00000476379.6 | c.610-2A>G | splice_acceptor_variant | 2 | NM_181426.2 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000118 AC: 29AN: 246154Hom.: 0 AF XY: 0.000127 AC XY: 17AN XY: 133378
GnomAD4 exome AF: 0.000110 AC: 160AN: 1457998Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83AN XY: 724902
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74350
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:3
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 | Invitae | Jan 11, 2024 | This sequence change affects an acceptor splice site in intron 5 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 (rs756235547, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 21131972, 22693285, 23891469). ClinVar contains an entry for this variant (Variation ID: 216140). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2017 | The c.610-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the CCDC39 gene. This mutation was confirmed in trans with a second splice alteration in an individual with Kartagener syndrome and axenomal disorganization on electron microscopy (Merveille AC et al. Nat. Genet., 2011 Jan;43:72-8). It was also identified in conjunction with a frameshift alteration in a primary ciliary dskinesia family with inner dynein arm defects and microtubule disorganization on electron microscopy (Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). 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. - |
Primary ciliary dyskinesia 14 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ciliary dyskinesia, primary, 14 (MIM#613807). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 31 heterozygotes, 0 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are inconclusive. (I) 0705 - No comparable canonical splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in homozygous and compound heterozygous state in multiple individuals with ciliary dyskinesia, primary, 14 (MIM#613807) (Clinvar; PMID: 22693285, 29748307, 30067075). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 13, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at