21-34364156-G-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_172201.2(KCNE2):c.-13+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000401 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_172201.2 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000401 AC: 61AN: 152180Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 6Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 2
GnomAD4 genome AF: 0.000401 AC: 61AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:3
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. -
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. -
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Long QT syndrome 6 Uncertain:2
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. -
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. -
Atrial fibrillation, familial, 4;C3150953:Long QT syndrome 6 Uncertain:1
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Congenital long QT syndrome Uncertain:1
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Atrial fibrillation, familial, 4 Uncertain:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at