14-62950156-G-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_139318.5(KCNH5):c.1346C>T(p.Ser449Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
KCNH5
NM_139318.5 missense
NM_139318.5 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
KCNH5 (HGNC:6254): (potassium voltage-gated channel subfamily H member 5) This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNH5. . Gene score misZ 2.509 (greater than the threshold 3.09). Trascript score misZ 3.7308 (greater than threshold 3.09). GenCC has associacion of gene with infantile-onset epilepsy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.8
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH5 | NM_139318.5 | c.1346C>T | p.Ser449Leu | missense_variant | 7/11 | ENST00000322893.12 | NP_647479.2 | |
KCNH5 | NM_172375.3 | c.1346C>T | p.Ser449Leu | missense_variant | 7/10 | NP_758963.1 | ||
KCNH5 | XM_047431275.1 | c.1346C>T | p.Ser449Leu | missense_variant | 7/10 | XP_047287231.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH5 | ENST00000322893.12 | c.1346C>T | p.Ser449Leu | missense_variant | 7/11 | 1 | NM_139318.5 | ENSP00000321427.7 | ||
KCNH5 | ENST00000420622.6 | c.1346C>T | p.Ser449Leu | missense_variant | 7/10 | 1 | ENSP00000395439.2 | |||
KCNH5 | ENST00000394964.3 | n.1511C>T | non_coding_transcript_exon_variant | 7/7 | 1 | |||||
KCNH5 | ENST00000394968.2 | c.1172C>T | p.Ser391Leu | missense_variant | 7/11 | 2 | ENSP00000378419.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152002Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250952Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135604
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GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461630Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727120
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152002Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74242
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 449 of the KCNH5 protein (p.Ser449Leu). This variant is present in population databases (rs369774413, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KCNH5-related conditions. ClinVar contains an entry for this variant (Variation ID: 572837). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;P;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at