rs751191119
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_017950.4(CCDC40):c.2183_2184del(p.Gly728AlafsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,954 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 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
CCDC40
NM_017950.4 frameshift
NM_017950.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.07
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 12 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 17-80084934-AGG-A is Pathogenic according to our data. Variant chr17-80084934-AGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 454883.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CCDC40 | NM_017950.4 | c.2183_2184del | p.Gly728AlafsTer27 | frameshift_variant | 13/20 | ENST00000397545.9 | |
CCDC40 | NM_001243342.2 | c.2183_2184del | p.Gly728AlafsTer27 | frameshift_variant | 13/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CCDC40 | ENST00000397545.9 | c.2183_2184del | p.Gly728AlafsTer27 | frameshift_variant | 13/20 | 5 | NM_017950.4 | P2 | |
CCDC40 | ENST00000574799.5 | n.1720_1721del | non_coding_transcript_exon_variant | 9/16 | 1 | ||||
CCDC40 | ENST00000374877.7 | c.2183_2184del | p.Gly728AlafsTer27 | frameshift_variant | 13/18 | 5 | A2 | ||
CCDC40 | ENST00000572253.5 | n.810_811del | non_coding_transcript_exon_variant | 2/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000281 AC: 7AN: 248972Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135110
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461764Hom.: 0 AF XY: 0.0000303 AC XY: 22AN XY: 727166
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74364
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2017 | This sequence change creates a premature translational stop signal (p.Gly728Alafs*27) in the CCDC40 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs751191119, ExAC 0.02%). This variant has not been reported in the literature in individuals with CCDC40-related disease. Loss-of-function variants in CCDC40 are known to be pathogenic (PMID: 21131974, 22693285, 23255504). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at