chr7-150950246-C-A
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.2320G>T(p.Asp774Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
KCNH2
NM_000238.4 missense
NM_000238.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 7.90
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 Pathogenic. Variant got 16 ACMG points.
PM1
In a binding_site (size 100) in uniprot entity KCNH2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000238.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 7-150950246-C-A is Pathogenic according to our data. Variant chr7-150950246-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150950246-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2320G>T | p.Asp774Tyr | missense_variant | 9/15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2320G>T | p.Asp774Tyr | missense_variant | 9/15 | 1 | NM_000238.4 | ENSP00000262186.5 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461044Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0AN XY: 726780
GnomAD4 exome
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39
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GnomAD4 genome Cov.: 30
GnomAD4 genome
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30
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 08, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2017 | The D774Y likely pathogenic variant in the KCNH2 gene has been reported previously in multiple unrelated patients with LQTS and has not been detected in over 1,500 reference alleles (Tester et al., 2005; Chung et al., 2007; Kapplinger et al, 2009). In addition, Obeyesekere et al. (2012), observed the D774Y variant in three individuals with a history of sudden cardiac death and prolonged end-recovery QTc.D774Y occurs in the S6/cyclic nucleotide-binding domain of the resultant protein, where many other pathogenic missense variants have been reported in association with LQTS (Stenson et al., 2014). According to the NHLBI Exome Sequencing Project, D774Y was not observed in approximately 6,500 individuals from European and African American backgrounds, indicating that it is not a common variant in these populations. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the D774Y variant results in a conservative amino acid substitution, which is not likely to impact secondary structure as these residues share similar properties.In summary, the D774Y variant is a strong candidate to be pathogenic - |
Long QT syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Apr 20, 2015 | - - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 08, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 774 of the KCNH2 protein (p.Asp774Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 15840476, 17905336, 22429796). ClinVar contains an entry for this variant (Variation ID: 67385). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810). For these reasons, this variant has been classified as Pathogenic. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:17905336;PMID:19716085;PMID:22429796). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;.
Vest4
MutPred
0.93
.;Gain of catalytic residue at L769 (P = 0.0497);.;
MVP
MPC
2.4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at