7-150948446-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate
The NM_000238.4(KCNH2):āc.2690A>Gā(p.Lys897Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000102 in 981,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K897M) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense, splice_region
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.2690A>G | p.Lys897Arg | missense_variant, splice_region_variant | 11/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2690A>G | p.Lys897Arg | missense_variant, splice_region_variant | 11/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000330883.9 | c.1670A>G | p.Lys557Arg | missense_variant, splice_region_variant | 7/11 | 1 | |||
KCNH2 | ENST00000684241.1 | n.3523A>G | splice_region_variant, non_coding_transcript_exon_variant | 9/13 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 6AN: 116716Hom.: 0 Cov.: 27 FAILED QC
GnomAD3 exomes AF: 0.0000126 AC: 3AN: 238268Hom.: 0 AF XY: 0.0000154 AC XY: 2AN XY: 130116
GnomAD4 exome AF: 0.00000102 AC: 1AN: 981826Hom.: 0 Cov.: 28 AF XY: 0.00000201 AC XY: 1AN XY: 498334
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000514 AC: 6AN: 116724Hom.: 0 Cov.: 27 AF XY: 0.0000532 AC XY: 3AN XY: 56416
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 25, 2023 | This missense variant replaces lysine with arginine at codon 897 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not change channel function in vitro (PMID: 34002542). This variant has not been reported in individuals affected with KCNH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at