ClinVar Genomic variation as it relates to human health
NM_172201.2(KCNE2):c.-13+5G>A
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_172201.2(KCNE2):c.-13+5G>A
Variation ID: 190793 Accession: VCV000190793.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.11 21: 34364156 (GRCh38) [ NCBI UCSC ] 21: 35736455 (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 6, 2016 Mar 26, 2023 Jul 25, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172201.2:c.-13+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000021.9:g.34364156G>A NC_000021.8:g.35736455G>A NG_008804.1:g.5133G>A LRG_291:g.5133G>A LRG_291t1:c.-13+5G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000021.9:34364155:G:A
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00046
The Genome Aggregation Database (gnomAD) 0.00043
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00040
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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KCNE2 | - | - |
GRCh38 GRCh37 |
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LOC105372791 | - | - | - | GRCh38 | - | 168 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000288510.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000331921.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 25, 2022 | RCV000381892.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 28, 2022 | RCV000505711.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 20, 2021 | RCV002485074.1 |
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
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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
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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
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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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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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Romano-Ward Syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000435616.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Uncertain significance
(Aug 14, 2018)
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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: SCV000223512.5
First in ClinVar: May 23, 2015 Last updated: Sep 26, 2017 |
Comment:
The c.-13+5 G>A variant of uncertain significance in the 5'UTR of the KCNE2 gene has been reported in two unrelated individuals tested for LQTS at … (more)
The c.-13+5 G>A variant of uncertain significance in the 5'UTR of the KCNE2 gene has been reported in two unrelated individuals tested for LQTS at GeneDx and was absent from 200 Caucasian and 100 African American healthy control individuals (Lieve et al., 2013). One of these individuals also harbored a variant in the KCNH2 gene that was expected to contribute to disease (Lieve et al., 2013). The c.-13+5 G>A variant has also been identified in several additional individuals referred for arrhythmia testing at GeneDx, however familial segregation information was either unavailable or uninformative. Additional data from large control populations were not sufficient to assess whether c.-13+5 G>A may be a common benign variant in the general population (Lek et al., 2016). This single nucleotide substitution occurs in the splice donor site of intron 1, and exon 1 is a non-coding exon. In addition, the guanine (G) is conserved at this position across vertebrate species. In silico analysis using two different splice algorithms predicts that this variant significantly reduces the quality of this splice site, while a third algorithm showed only a modest change. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. In addition, no other splice site variants in the KCNE2 gene have been reported in the Human Gene Mutation Database in association with KCNE2-related disorders (Stenson et al., 2014) and the majority of pathogenic variants in the KCNE2 gene are missense changes, indicating haploinsufficiency may not be sufficient to cause disease. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Atrial fibrillation, familial, 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000435618.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 6
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000435617.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jul 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 6
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001532936.2
First in ClinVar: Mar 22, 2021 Last updated: Mar 26, 2023 |
Comment:
This variant occurs in a non-coding region of the KCNE2 gene. It does not change the encoded amino acid sequence of the KCNE2 protein. This … (more)
This variant occurs in a non-coding region of the KCNE2 gene. It does not change the encoded amino acid sequence of the KCNE2 protein. This variant is present in population databases (rs786205806, gnomAD 1.0%). This variant has been observed in individual(s) with long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 190793). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Atrial fibrillation, familial, 4
Long QT syndrome 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002777475.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jun 28, 2022)
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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: SCV003800464.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The KCNE2 c.-13+5G>A variant (rs786205806) is reported in the literature in individuals affected with long QT syndrome (Lieve 2013), but at least one individual has … (more)
The KCNE2 c.-13+5G>A variant (rs786205806) is reported in the literature in individuals affected with long QT syndrome (Lieve 2013), but at least one individual has another molecular explanation for disease (Roberts 2017). This variant is also reported in ClinVar (Variation ID: 190793), and is found in the general population with an allele frequency of 0.013% (4/31398 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing weakening the nearby canonical donor splice site. However, this splice site is in a non-coding exon, and variants affecting splicing in KCNE2 have not been reported in association with disease. Thus, without functional studies the effect on splicing is unknown. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Lieve KV et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. PMID: 23631430. Roberts JD et al. Loss-of-Function KCNE2 Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation? Circ Arrhythm Electrophysiol. 2017 Aug;10(8):e005282. PMID: 28794082. (less)
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Uncertain significance
(Sep 04, 2014)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924806.1
First in ClinVar: Jun 29, 2019 Last updated: Jun 29, 2019 |
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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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Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. | Lieve KV | Genetic testing and molecular biomarkers | 2013 | PMID: 23631430 |
Text-mined citations for rs786205806 ...
HelpRecord last updated Oct 15, 2023
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.