14-62707603-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_139318.5(KCNH5):c.2872C>T(p.Pro958Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000389 in 1,541,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH5 | NM_139318.5 | c.2872C>T | p.Pro958Ser | missense_variant | 11/11 | ENST00000322893.12 | NP_647479.2 | |
KCNH5 | NM_172375.3 | c.*839C>T | 3_prime_UTR_variant | 10/10 | NP_758963.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH5 | ENST00000322893.12 | c.2872C>T | p.Pro958Ser | missense_variant | 11/11 | 1 | NM_139318.5 | ENSP00000321427 | P1 | |
KCNH5 | ENST00000420622.6 | c.*839C>T | 3_prime_UTR_variant | 10/10 | 1 | ENSP00000395439 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152050Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000292 AC: 6AN: 205424Hom.: 0 AF XY: 0.0000368 AC XY: 4AN XY: 108738
GnomAD4 exome AF: 0.0000396 AC: 55AN: 1389296Hom.: 0 Cov.: 29 AF XY: 0.0000411 AC XY: 28AN XY: 681102
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74256
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 26, 2022 | The c.2872C>T (p.P958S) alteration is located in exon 11 (coding exon 11) of the KCNH5 gene. This alteration results from a C to T substitution at nucleotide position 2872, causing the proline (P) at amino acid position 958 to be replaced by a serine (S). 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 | Labcorp Genetics (formerly Invitae), Labcorp | Oct 12, 2022 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 958 of the KCNH5 protein (p.Pro958Ser). This variant is present in population databases (rs141160972, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with KCNH5-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 1385516). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at