rs45610936
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2
The NM_172201.2(KCNE2):c.369_370del(p.Ter124IlefsTer15) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P123P) has been classified as Likely benign.
Frequency
Consequence
NM_172201.2 frameshift, stop_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNE2 | NM_172201.2 | c.369_370del | p.Ter124IlefsTer15 | frameshift_variant, stop_lost | 2/2 | ENST00000290310.4 | |
LOC105372791 | XR_937683.3 | n.1006_1007del | non_coding_transcript_exon_variant | 2/2 | |||
LOC105372791 | XR_007067848.1 | n.1041_1042del | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNE2 | ENST00000290310.4 | c.369_370del | p.Ter124IlefsTer15 | frameshift_variant, stop_lost | 2/2 | 1 | NM_172201.2 | P1 | |
ENST00000440403.2 | n.441_442del | non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000797 AC: 20AN: 251094Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135840
GnomAD4 exome AF: 0.0000862 AC: 126AN: 1461534Hom.: 0 AF XY: 0.0000811 AC XY: 59AN XY: 727082
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74356
ClinVar
Submissions by phenotype
Atrial fibrillation, familial, 4;C3150953:Long QT syndrome 6 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 20, 2022 | The c.369_370delCT variant has previously been reported in an individual with sudden infant death syndrome [PMID: 29544605] and in a patient with LQT phenotype [PMID:19716085]. The variant was also observed in another patient with LQT phenotype as well as in three asymptomatic relatives with normal QT interval [PMID: 28794082]. This variant has been deposited in ClinVar [ClinVar ID: 190797] as a Variant of Uncertain Significance. The variant c.369_370delCT is observed in 51 alleles (~ 0.009% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.369_370delCT variant is located in the last exon of this 2-exon gene, replaces the canonical stop codon with Isoleucine residue and is predicted to extend the length of KCNE2 protein at the C-terminus by an additional 14 amino acids. Functional consequences of these predicted additional amino acids are unknown at this time. Based on available evidence, this c.369_370delCT p.(Ter124IleextTer?) variant identified in KCNE2 gene is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 23, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2022 | Reported in association with LQTS, SCD, and SIDS (Kapplinger et al., 2009; Roberts et al., 2017; Tester et al., 2018); however, it was shown to segregate in three asymptomatic relatives with normal QTc intervals (Roberts et al., 2017); Normal stop codon changed to an isoleucine codon, leading to the addition of 14 amino acids at the C-terminus; This variant is associated with the following publications: (PMID: 29544605, 28794082, 19716085) - |
KCNE2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 26, 2018 | The KCNE2 c.369_370delCT (p.Ter124Ile) variant is a stop-loss variant that is predicted to result in an elongation of the protein. The p.Ter124Ile variant has been reported in a single study and found in one individual referred for long QT syndrome genetic testing (Kapplinger et al. 2009). Four other genes, including the three major contributors to long QT syndrome, were also screened for variants in this patient. The variant was absent from over 1300 healthy control individuals and is reported at a frequency of 0.000203 in the Latino population of the Genome Aggregation Database. The p.Ter124Ile variant has not been reported in the literature in association with familial atrial fibrillation. Based on the evidence and the potential impact of stop-lost variants, the p.Ter124Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for KCNE2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Long QT syndrome 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | This sequence change disrupts the translational stop signal of the KCNE2 mRNA. It is expected to extend the length of the KCNE2 protein by 14 additional amino acid residues. This variant is present in population databases (rs45610936, gnomAD 0.02%). This protein extension has been observed in individual(s) with sudden unexplained death or clinical features of long QT syndrome (PMID: 19716085, 28794082, 29544605). This variant is also known as Pro123fsTer16. ClinVar contains an entry for this variant (Variation ID: 190797). 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 may create or strengthen a splice site. 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at