ClinVar Genomic variation as it relates to human health
NM_001199397.3(NEK1):c.1226G>A (p.Trp409Ter)
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_001199397.3(NEK1):c.1226G>A (p.Trp409Ter)
Variation ID: 446672 Accession: VCV000446672.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q33 4: 169561520 (GRCh38) [ NCBI UCSC ] 4: 170482671 (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 Dec 10, 2017 Mar 10, 2024 May 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001199397.3:c.1226G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001186326.1:p.Trp409Ter nonsense NM_001199398.3:c.1226G>A NP_001186327.1:p.Trp409Ter nonsense NM_001199399.3:c.1191+167G>A intron variant NM_001199400.3:c.1226G>A NP_001186329.1:p.Trp409Ter nonsense NM_001374418.1:c.1226G>A NP_001361347.1:p.Trp409Ter nonsense NM_001374419.1:c.1226G>A NP_001361348.1:p.Trp409Ter nonsense NM_001374420.1:c.1175G>A NP_001361349.1:p.Trp392Ter nonsense NM_001374421.1:c.1140+312G>A intron variant NM_001374422.1:c.1226G>A NP_001361351.1:p.Trp409Ter nonsense NM_001374423.1:c.1226G>A NP_001361352.1:p.Trp409Ter nonsense NM_012224.4:c.1226G>A NP_036356.1:p.Trp409Ter nonsense NR_164630.1:n.1740G>A non-coding transcript variant NR_164631.1:n.1607G>A non-coding transcript variant NC_000004.12:g.169561520C>T NC_000004.11:g.170482671C>T NG_027982.1:g.56108G>A - Protein change
- W409*, W392*
- Other names
- 1226G-A
- Canonical SPDI
- NC_000004.12:169561519:C: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 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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NEK1 | - | - |
GRCh38 GRCh37 |
748 | 820 |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 29, 2023 | RCV000515987.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 24, 2019 | RCV000756417.10 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 20, 2024 | RCV003766906.2 |
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
(Jul 19, 2017)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884226.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
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Likely pathogenic
(Apr 24, 2019)
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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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GeneDx
Accession: SCV001769578.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 27530628, 27455347, 29068549) (less)
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Pathogenic
(Dec 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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Short-rib thoracic dysplasia 6 with or without polydactyly
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018293.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(May 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Short-rib thoracic dysplasia 6 with or without polydactyly
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002316176.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This premature translational stop signal has been observed in individual(s) with clinical features of a skeletal ciliopathy (PMID: 27530628, 29068549). It has also been observed … (more)
This premature translational stop signal has been observed in individual(s) with clinical features of a skeletal ciliopathy (PMID: 27530628, 29068549). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Trp409*) in the NEK1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. ClinVar contains an entry for this variant (Variation ID: 446672). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this premature translational stop signal results in skipping of exon 15, but is expected to preserve the integrity of the reading-frame (PMID: 27530628). (less)
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Pathogenic
(Jun 01, 2017)
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no assertion criteria provided
Method: research
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Short-rib thoracic dysplasia 6 with or without polydactyly
Affected status: yes
Allele origin:
unknown
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Dan Cohn Lab, University Of California Los Angeles
Accession: SCV000612098.1
First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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short-rib polydactyly syndrome type II
Affected status: yes
Allele origin:
inherited
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479757.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
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Pathogenic
(Feb 20, 2024)
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no assertion criteria provided
Method: literature only
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OROFACIODIGITAL SYNDROME II (1 family)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV004697436.2
First in ClinVar: Feb 28, 2024 Last updated: Mar 10, 2024 |
Comment on evidence:
For discussion of the c.1226G-A transition (c.1226G-A, NM_012224.2) in exon 15 of the NEK1 gene that was found in compound heterozygous state in 2 brothers … (more)
For discussion of the c.1226G-A transition (c.1226G-A, NM_012224.2) in exon 15 of the NEK1 gene that was found in compound heterozygous state in 2 brothers with orofaciodigital syndrome II (OFD2; 252100) by Monroe et al. (2016), see 604588.0013. (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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Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. | Zhang W | Human mutation | 2018 | PMID: 29068549 |
Compound heterozygous NEK1 variants in two siblings with oral-facial-digital syndrome type II (Mohr syndrome). | Monroe GR | European journal of human genetics : EJHG | 2016 | PMID: 27530628 |
Text-mined citations for rs985064686 ...
HelpRecord last updated Mar 17, 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.