rs1553344875
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_172362.3(KCNH1):c.1705G>A(p.Val569Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V569V) has been classified as Likely benign.
Frequency
Consequence
NM_172362.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH1 | NM_172362.3 | c.1705G>A | p.Val569Met | missense_variant | 9/11 | ENST00000271751.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH1 | ENST00000271751.10 | c.1705G>A | p.Val569Met | missense_variant | 9/11 | 2 | NM_172362.3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461752Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727148
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2022 | The c.1705G>A (p.V569M) alteration is located in exon 9 (coding exon 9) of the KCNH1 gene. This alteration results from a G to A substitution at nucleotide position 1705, causing the valine (V) at amino acid position 569 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The p.V569M amino acid is located in the cyclic nucleotide-binding domain of the KCNH1 protein. Based on internal structural analysis, p.V569M does not decrease the stability of the protein structure and there are no other pathogenic alterations nearby (Whicher, 2016). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at