rs150275982
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2
The NM_000238.4(KCNH2):c.1581G>A(p.Ala527=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,588,234 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00089 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000090 ( 1 hom. )
Consequence
KCNH2
NM_000238.4 synonymous
NM_000238.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.90
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 Benign. Variant got -17 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
Variant 7-150951812-C-T is Benign according to our data. Variant chr7-150951812-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 200224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=-3.9 with no splicing effect.
BS2
?
High AC in GnomAd4 at 135 AD,Digenic gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1581G>A | p.Ala527= | synonymous_variant | 7/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.1581G>A | p.Ala527= | synonymous_variant | 7/15 | 1 | NM_000238.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000887 AC: 135AN: 152220Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000243 AC: 57AN: 234786Hom.: 1 AF XY: 0.000151 AC XY: 19AN XY: 126166
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GnomAD4 exome AF: 0.0000898 AC: 129AN: 1435896Hom.: 1 Cov.: 36 AF XY: 0.0000789 AC XY: 56AN XY: 709980
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GnomAD4 genome ? AF: 0.000886 AC: 135AN: 152338Hom.: 0 Cov.: 34 AF XY: 0.000846 AC XY: 63AN XY: 74490
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 03, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Long QT syndrome 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 22, 2021 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2015 | 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. - |
Cardiac arrhythmia Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 30, 2018 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at