rs863223325
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_033124.5(CCDC65):c.877_878delAT(p.Ile293ProfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_033124.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CCDC65 | NM_033124.5 | c.877_878delAT | p.Ile293ProfsTer2 | frameshift_variant | Exon 6 of 8 | ENST00000320516.5 | NP_149115.2 | |
CCDC65 | NM_001286957.2 | c.448_449delAT | p.Ile150ProfsTer2 | frameshift_variant | Exon 6 of 8 | NP_001273886.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CCDC65 | ENST00000320516.5 | c.877_878delAT | p.Ile293ProfsTer2 | frameshift_variant | Exon 6 of 8 | 1 | NM_033124.5 | ENSP00000312706.4 | ||
ENSG00000272822 | ENST00000398092.4 | c.385-14844_385-14843delTA | intron_variant | Intron 4 of 4 | 3 | ENSP00000438507.1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000203 AC: 51AN: 251484Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135922
GnomAD4 exome AF: 0.000130 AC: 190AN: 1461862Hom.: 0 AF XY: 0.000135 AC XY: 98AN XY: 727230
GnomAD4 genome AF: 0.000151 AC: 23AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74328
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 27 Pathogenic:3
This sequence change creates a premature translational stop signal (p.Ile293Profs*2) in the CCDC65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CCDC65 are known to be pathogenic (PMID: 23991085, 24094744). This variant is present in population databases (rs748630203, gnomAD 0.4%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23991085, 24094744). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 23991085, 24094744). This variant is also known as 876_877delAT. ClinVar contains an entry for this variant (Variation ID: 88685). For these reasons, this variant has been classified as Pathogenic. -
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CCDC65 c.877_878del has been reported in the homozygous state in multiple individuals with primary ciliary dyskinesia. This variant (rs1272967209) has an entry in ClinVar and has been identified in a large population dataset. The minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the Ashkenazi Jewish subpopulation (gnomAD: 45/10370 alleles; 0.4339%, no homozygotes). This frameshift variant results in a premature stop codon in exon 6 of 8 likely leading to nonsense-mediated decay and lack of protein production. We consider CCDC65 c.877_878del to be pathogenic. -
Primary ciliary dyskinesia Pathogenic:1
The p.Ile293fs variant in CCDC65 has been previously reported in 3 Ashkenazi Jew ish individuals with primary ciliary dyskinesia (PCD) and segregated with diseas e in 1 affected family member (Austin-Tse 2013, Horani 2013). All of these indiv iduals were homozygous for the variant. This variant has also been identified in 20/66728 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org) and in 0.14% (3/2070) of chromosomes from an Ashkenazi Jewish control cohort (Fedick 2015). Although this variant has been seen in the general population, its frequency is still low enough to be consistent with a r ecessive carrier frequency. The p.Ile293fs variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 293 and leads to a premature termination codon 2 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. In vitro studie s have demonstrated that the CCDC65 protein was absent in cells derived from an individual homozygous for this variant (Horani 2013). Functional studies in huma n cell lines and the zebrafish model provided some evidence that loss of functio n of the CCDC65 gene may cause cilia motility defects (Horani 2013, Austin-Tse 2 013), though these types of assays may not accurately reflect biological functio n. The p.Ile293fs variant is currently the only variant in CCDC65 gene that has been reported in individuals with PCD, therefore additional studies are needed t o fully understand the role of the CCDC65 gene in disease. In summary, although additional studies are required to fully establish its clinical significance, th e p.Ile293fs variant is likely pathogenic. -
not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 24094744, 23991085, 34693619) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at