rs587778819
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017950.4(CCDC40):c.2824_2825insCTGT(p.Arg942fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000035 ( 0 hom. )
Consequence
CCDC40
NM_017950.4 frameshift
NM_017950.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.25
Genes affected
CCDC40 (HGNC:26090): (coiled-coil domain 40 molecular ruler complex subunit) This gene encodes a protein that is necessary for motile cilia function. It functions in correct left-right axis formation by regulating the assembly of the inner dynein arm and the dynein regulatory complexes, which control ciliary beat. Mutations in this gene cause ciliary dyskinesia type 15, a disorder due to defects in cilia motility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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;
PP5
Variant 17-80089876-A-ACTGT is Pathogenic according to our data. Variant chr17-80089876-A-ACTGT is described in ClinVar as [Pathogenic]. Clinvar id is 194774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152274Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249426Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135364
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GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27AN XY: 727232
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152274Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74400
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 15 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000194774 / PMID: 31443223). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 18, 2022 | ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated, PM3 moderated - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 29, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 05, 2021 | - - |
Primary ciliary dyskinesia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 05, 2024 | This sequence change creates a premature translational stop signal (p.Arg942Thrfs*57) in the CCDC40 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC40 are known to be pathogenic (PMID: 21131974, 22693285, 23255504). This variant is present in population databases (rs587778819, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with primary ciliary dyskinesia (PMID: 31443223; internal data). ClinVar contains an entry for this variant (Variation ID: 194774). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2021 | The c.2824_2825insCTGT variant, located in coding exon 17 of the CCDC40 gene, results from an insertion of 4 nucleotides at position 2824, causing a translational frameshift with a predicted alternate stop codon (p.R942Tfs*57). This mutation has been identified in multiple homozygous and compound heterozygous individuals with primary ciliary dyskinesia (PCD) (Pereira R et al. Cells, 2019 08;8:; Fassad MR et al. Clin Genet, 2020 03;97:509-515; Blanchon S et al. J Med Genet, 2020 04;57:237-244; Fassad MR et al. J Med Genet, 2020 05;57:322-330). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 06, 2014 | - - |
Kartagener syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS) | - | Bioinformatic tools predict as potentially pathogenic. We found other potential pathogenic variant in same gene, CCDC40: NM_017950.3:c.1989+1G>A - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at