ClinVar Genomic variation as it relates to human health
NM_017950.4(CCDC40):c.2824_2825insCTGT (p.Arg942fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017950.4(CCDC40):c.2824_2825insCTGT (p.Arg942fs)
Variation ID: 194774 Accession: VCV000194774.20
- Type and length
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Insertion, 4 bp
- Location
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Cytogenetic: 17q25.3 17: 80089876-80089877 (GRCh38) [ NCBI UCSC ] 17: 78063675-78063676 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 28, 2015 May 1, 2024 Aug 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017950.4:c.2824_2825insCTGT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060420.2:p.Arg942fs frameshift NM_001243342.2:c.2824_2825insCTGT NP_001230271.1:p.Arg942fs frameshift NC_000017.11:g.80089876_80089877insCTGT NC_000017.10:g.78063675_78063676insCTGT NG_029761.1:g.58245_58246insCTGT - Protein change
- R942fs
- Other names
- -
- Canonical SPDI
- NC_000017.11:80089876::CTGT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- variation affecting protein Variation Ontology [VariO:0002]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CCDC40 | - | - |
GRCh38 GRCh38 GRCh37 |
947 | 989 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jun 6, 2014 | RCV000175218.5 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV000578183.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 18, 2023 | RCV000538390.13 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV001781534.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 15
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002573107.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Nonproductive cough (present) , Tachypnea (present) , Hypoxemia (present)
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Pathogenic
(Mar 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 15
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807090.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated, PM3 moderated
Number of individuals with the variant: 1
Clinical Features:
Proportionate short stature (present) , Neonatal respiratory distress (present) , Decreased body weight (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Sep 29, 2020)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 15
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016964.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000624392.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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; Invitae). ClinVar contains an entry for this variant (Variation ID: 194774). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002752226.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jun 06, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000226663.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary ciliary dyskinesia 15
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002791784.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Kartagener syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS)
Additional submitter:
Molecular Genetics Unit, Centre of Medical Genetics Dr. Jacinto de Magalhães (CGMJM), CHP
Accession: SCV000579339.1
First in ClinVar: Feb 03, 2018 Last updated: Feb 03, 2018 |
Comment:
Bioinformatic tools predict as potentially pathogenic. We found other potential pathogenic variant in same gene, CCDC40: NM_017950.3:c.1989+1G>A
Age: 0-9 years
Sex: female
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein
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Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS)
Additional submitter:
Molecular Genetics Unit, Centre of Medical Genetics Dr. Jacinto de Magalhães (CGMJM), CHP
Accession: SCV000579339.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. | Fassad MR | Journal of medical genetics | 2020 | PMID: 31879361 |
Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia. | Blanchon S | Journal of medical genetics | 2020 | PMID: 31772028 |
Clinical and genetic spectrum in 33 Egyptian families with suspected primary ciliary dyskinesia. | Fassad MR | Clinical genetics | 2020 | PMID: 31650533 |
Clinical and Genetic Analysis of Children with Kartagener Syndrome. | Pereira R | Cells | 2019 | PMID: 31443223 |
Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. | Antony D | Human mutation | 2013 | PMID: 23255504 |
Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia. | Blanchon S | Journal of medical genetics | 2012 | PMID: 22693285 |
The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. | Becker-Heck A | Nature genetics | 2011 | PMID: 21131974 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CCDC40 | - | - | - | - |
Text-mined citations for rs587778819 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.