rs864622174
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000238.4(KCNH2):βc.3060delβ(p.Ser1021AlafsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,325,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes π: 0.0000015 ( 0 hom. )
Consequence
KCNH2
NM_000238.4 frameshift
NM_000238.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.174
Genes affected
KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 7-150947419-TG-T is Pathogenic according to our data. Variant chr7-150947419-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150947419-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.3060del | p.Ser1021AlafsTer36 | frameshift_variant | 13/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.3060del | p.Ser1021AlafsTer36 | frameshift_variant | 13/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000330883.9 | c.2040del | p.Ser681AlafsTer36 | frameshift_variant | 9/11 | 1 | |||
KCNH2 | ENST00000684241.1 | n.3893del | non_coding_transcript_exon_variant | 11/13 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000151 AC: 2AN: 1325136Hom.: 0 Cov.: 37 AF XY: 0.00000152 AC XY: 1AN XY: 656690
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | deCODE genetics, Amgen | Jul 21, 2023 | The variant NM_000238.4:c.3060del (chr7:150947419) in KCNH2 was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2023 | Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23631430) - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2017 | This variant has been reported in one individual with long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 219597). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser1021Alafs*36) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at