chr14-62950163-T-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_139318.5(KCNH5):āc.1339A>Gā(p.Met447Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,740 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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M447T) has been classified as Uncertain significance.
Frequency
Consequence
NM_139318.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH5 | NM_139318.5 | c.1339A>G | p.Met447Val | missense_variant | 7/11 | ENST00000322893.12 | |
KCNH5 | NM_172375.3 | c.1339A>G | p.Met447Val | missense_variant | 7/10 | ||
KCNH5 | XM_047431275.1 | c.1339A>G | p.Met447Val | missense_variant | 7/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH5 | ENST00000322893.12 | c.1339A>G | p.Met447Val | missense_variant | 7/11 | 1 | NM_139318.5 | P1 | |
KCNH5 | ENST00000420622.6 | c.1339A>G | p.Met447Val | missense_variant | 7/10 | 1 | |||
KCNH5 | ENST00000394964.3 | n.1504A>G | non_coding_transcript_exon_variant | 7/7 | 1 | ||||
KCNH5 | ENST00000394968.2 | c.1165A>G | p.Met389Val | missense_variant | 7/11 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152066Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251016Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135628
GnomAD4 exome AF: 0.0000876 AC: 128AN: 1461674Hom.: 0 Cov.: 31 AF XY: 0.0000743 AC XY: 54AN XY: 727128
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152066Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74260
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 13, 2024 | The c.1339A>G (p.M447V) alteration is located in exon 7 (coding exon 7) of the KCNH5 gene. This alteration results from a A to G substitution at nucleotide position 1339, causing the methionine (M) at amino acid position 447 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 447 of the KCNH5 protein (p.Met447Val). This variant is present in population databases (rs200506671, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of KCNH5-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 461386). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNH5 protein function with a negative predictive value of 95%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at