chr15-84817382-CG-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_020778.5(ALPK3):c.-66del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,218,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
ALPK3
NM_020778.5 5_prime_UTR
NM_020778.5 5_prime_UTR
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.796
Genes affected
ALPK3 (HGNC:17574): (alpha kinase 3) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in cardiac muscle cell development. Predicted to be active in nucleus. Implicated in hypertrophic cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALPK3 | NM_020778.5 | c.-66del | 5_prime_UTR_variant | 1/14 | ENST00000258888.6 | NP_065829.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALPK3 | ENST00000258888.6 | c.-66del | 5_prime_UTR_variant | 1/14 | 1 | NM_020778.5 | ENSP00000258888 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000239 AC: 36AN: 150594Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000168 AC: 18AN: 1068288Hom.: 0 Cov.: 49 AF XY: 0.0000277 AC XY: 14AN XY: 505556
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GnomAD4 genome AF: 0.000239 AC: 36AN: 150698Hom.: 0 Cov.: 33 AF XY: 0.000204 AC XY: 15AN XY: 73642
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Ala181Profs*130) in the ALPK3 gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 203 has the potential to rescue this truncating variant. This variant is present in population databases (no rsID available, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of ALPK3-related conditions (PMID: 32480058). ClinVar contains an entry for this variant (Variation ID: 1487747). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2023 | The c.541delG variant, located in coding exon 1 of the ALPK3 gene, results from a deletion of one nucleotide at nucleotide position 541, causing a translational frameshift with a predicted alternate stop codon (p.A181Pfs*130). This variant was reported in one individual with dilated cardiomyopathy, who had a second ALPK3 variant also detected; however, phase information was not provided (Herkert JC et al. Am Heart J, 2020 07;225:108-119). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, based on data from gnomAD, several loss of function alterations in the first exon of ALPK3 (p.C64* and p.E148Qfs*8) are too frequent to cause disease given the incidence of pediatric cardiomyopathy. The abundance of nonsense and frameshift alleles in the first exon in population databases brings into question the pathogenicity of loss of function alterations in N-terminus of ALPK3 and suggests the possibility of an alternative start site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at