chr7-150951689-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000238.4(KCNH2):c.1704G>A(p.Trp568Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,826 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
KCNH2
NM_000238.4 stop_gained
NM_000238.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 7.72
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 7-150951689-C-T is Pathogenic according to our data. Variant chr7-150951689-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 200370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951689-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1704G>A | p.Trp568Ter | stop_gained | 7/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.1704G>A | p.Trp568Ter | stop_gained | 7/15 | 1 | NM_000238.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461826Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727222
GnomAD4 exome
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2
AN:
1461826
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34
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2
AN XY:
727222
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2015 | p.Trp568Stop (TGG>TGA):c.1704 G>A in exon 7 of the KCNH2 (aka HERG) gene (NM_000238.2)The Trp568Stop mutation in the KCNH2 gene has been reported in association with LQTS (Kapplinger J et al., 2009). This mutation was reported in one patient with LQTS and it was absent from 2,600 control alleles. The Trp568Stop mutation is predicted to cause loss of normal protein function either due to a prematurely truncated protein or absent protein product due to nonsense mediated mRNA decay. Other nonsense mutations in the KCNH2 gene have also been reported in association with LQTS.In summary, Trp568Stop mutation in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s). - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 15, 2017 | The p.W568* pathogenic mutation (also known as c.1704G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1704. This changes the amino acid from a tryptophan to a stop codon within coding exon 7. In a study of long QT syndrome clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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