ClinVar Genomic variation as it relates to human health
NM_017950.4(CCDC40):c.2712-1G>T
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.2712-1G>T
Variation ID: 407769 Accession: VCV000407769.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 78063562 (GRCh37) [ NCBI UCSC ] 17: 80089763 (GRCh38) [ 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 Oct 10, 2018 Mar 16, 2024 Nov 21, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017950.4:c.2712-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001243342.2:c.2712-1G>T splice acceptor NC_000017.11:g.80089763G>T NC_000017.10:g.78063562G>T NG_029761.1:g.58132G>T - Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:80089762:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00017
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 |
927 | 969 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2023 | RCV000465864.12 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2022 | RCV000779234.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2022 | RCV002223847.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV003902644.1 |
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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Likely pathogenic
(Oct 19, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000915786.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CCDC40 c.2712-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.2712-1G>T … (more)
The CCDC40 c.2712-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.2712-1G>T variant has been reported in two studies and is found in a total of five patients with inner dynein arm defects including three in a homozygous state and two in a compound heterozygous state (Antony et al. 2013; Blanchon et al. 2012). Two of the homozygotes are siblings (Antony et al. 2013). The variant is also found in four unaffected individuals in a heterozygous state (Antony et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000071 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, including the potential impact of splice acceptor variants, the c.2712-1G>T variant is classified as likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: yes
Allele origin:
germline
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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502605.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Mar 16, 2018)
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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: SCV002741000.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.2712-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 17 of the CCDC40 gene. This mutation … (more)
The c.2712-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 17 of the CCDC40 gene. This mutation was identified in two compound heterozygous and two homozygous individuals with primary ciliary dyskinesia (Blanchon S et al. J. Med. Genet., 2012 Jun;49:410-6; Antony D et al. Hum. Mutat., 2013 Mar;34:462-72). 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. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 11, 2022)
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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: SCV002786406.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jul 17, 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: SCV000547201.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 16 of the CCDC40 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 16 of the CCDC40 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 CCDC40 are known to be pathogenic (PMID: 21131974, 22693285, 23255504). This variant is present in population databases (rs370706991, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (PMID: 22693285, 23255504). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 407769). 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. (less)
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Pathogenic
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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CCDC40-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004727462.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The CCDC40 c.2712-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is documented causative for primary … (more)
The CCDC40 c.2712-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is documented causative for primary ciliary dyskinesia (PCD) (Blanchon et al. 2012. PubMed ID: 22693285). Biallelic pathogenic variants in CCDC40 are known to cause defects in inner dynein arm (IDA) assembly, as well as generalized axonemal disorganization (Becker-Heck et al. 2011. PubMed ID: 21131974; Antony et al. 2011. PubMed ID: 23255504). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78063562-G-T). Variants that disrupt the consensus splice acceptor site in CCDC40 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
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 |
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 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs370706991 ...
HelpRecord last updated Apr 15, 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.