rs199472869
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting
The NM_000238.4(KCNH2):āc.652A>Gā(p.Met218Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000672 in 1,488,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000060 ( 0 hom. )
Consequence
KCNH2
NM_000238.4 missense
NM_000238.4 missense
Scores
3
3
13
Clinical Significance
Conservation
PhyloP100: -0.424
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 Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.28888607).
BS2
?
High AC in GnomAdExome4 at 8 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.652A>G | p.Met218Val | missense_variant | 4/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.652A>G | p.Met218Val | missense_variant | 4/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000532957.5 | n.875A>G | non_coding_transcript_exon_variant | 4/9 | 2 | ||||
KCNH2 | ENST00000684241.1 | n.1485A>G | non_coding_transcript_exon_variant | 2/13 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151842Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000598 AC: 8AN: 1336718Hom.: 0 Cov.: 32 AF XY: 0.00000454 AC XY: 3AN XY: 660414
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151842Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74180
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jun 16, 2016 | - - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 13, 2021 | This sequence change replaces methionine with valine at codon 218 of the KCNH2 protein (p.Met218Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67516). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 13, 2023 | The p.M218V variant (also known as c.652A>G), located in coding exon 4 of the KCNH2 gene, results from an A to G substitution at nucleotide position 652. The methionine at codon 218 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in long QT syndrome cohorts; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Walsh R et al. Genet Med, 2021 Jan;23:47-58). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 01, 2021 | - - |
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:19716085). 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
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.
MutationTaster
Benign
N;N;N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Loss of stability (P = 0.0997);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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