rs199472878
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000238.4(KCNH2):c.830C>A(p.Ala277Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A277S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.830C>A | p.Ala277Asp | missense_variant | 4/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.830C>A | p.Ala277Asp | missense_variant | 4/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000532957.5 | n.1053C>A | non_coding_transcript_exon_variant | 4/9 | 2 | ||||
KCNH2 | ENST00000684241.1 | n.1663C>A | non_coding_transcript_exon_variant | 2/13 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151924Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1174242Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 566588
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151924Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74196
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2022 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 67533). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 277 of the KCNH2 protein (p.Ala277Asp). - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at