rs376158544
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP2PP3BS2
The NM_139318.5(KCNH5):c.1003G>A(p.Ala335Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000572 in 1,609,718 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 0.000040 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000059 ( 0 hom. )
Consequence
KCNH5
NM_139318.5 missense
NM_139318.5 missense
Scores
10
5
4
Clinical Significance
Conservation
PhyloP100: 7.90
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 Uncertain_significance. Variant got 0 ACMG points.
PM1
?
In a transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 20) in uniprot entity KCNH5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_139318.5
PP2
?
Missense variant where missense usually causes diseases, KCNH5
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.758
BS2
?
High AC in GnomAd4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH5 | NM_139318.5 | c.1003G>A | p.Ala335Thr | missense_variant | 7/11 | ENST00000322893.12 | |
KCNH5 | NM_172375.3 | c.1003G>A | p.Ala335Thr | missense_variant | 7/10 | ||
KCNH5 | XM_047431275.1 | c.1003G>A | p.Ala335Thr | missense_variant | 7/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH5 | ENST00000322893.12 | c.1003G>A | p.Ala335Thr | missense_variant | 7/11 | 1 | NM_139318.5 | P1 | |
KCNH5 | ENST00000420622.6 | c.1003G>A | p.Ala335Thr | missense_variant | 7/10 | 1 | |||
KCNH5 | ENST00000394964.3 | n.1168G>A | non_coding_transcript_exon_variant | 7/7 | 1 | ||||
KCNH5 | ENST00000394968.2 | c.829G>A | p.Ala277Thr | missense_variant | 7/11 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151798Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000202 AC: 5AN: 247776Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134038
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GnomAD4 exome AF: 0.0000590 AC: 86AN: 1457920Hom.: 0 Cov.: 32 AF XY: 0.0000565 AC XY: 41AN XY: 725376
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GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 151798Hom.: 0 Cov.: 31 AF XY: 0.0000675 AC XY: 5AN XY: 74110
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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 | Invitae | Oct 10, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 335 of the KCNH5 protein (p.Ala335Thr). This variant is present in population databases (rs376158544, gnomAD 0.004%). 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: 461384). 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
Pathogenic
DEOGEN2
Uncertain
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Pathogenic
Sift
Benign
D;T;D
Sift4G
Uncertain
T;T;D
Polyphen
P;P;P
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at