rs120074114
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_000483.5(APOC2):āc.122A>Cā(p.Lys41Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00086 in 1,614,184 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000483.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APOC2 | NM_000483.5 | c.122A>C | p.Lys41Thr | missense_variant | 3/4 | ENST00000252490.7 | |
APOC4-APOC2 | NR_037932.1 | n.1329A>C | non_coding_transcript_exon_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APOC2 | ENST00000252490.7 | c.122A>C | p.Lys41Thr | missense_variant | 3/4 | 2 | NM_000483.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000690 AC: 105AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000692 AC: 174AN: 251452Hom.: 0 AF XY: 0.000736 AC XY: 100AN XY: 135896
GnomAD4 exome AF: 0.000878 AC: 1283AN: 1461880Hom.: 4 Cov.: 32 AF XY: 0.000875 AC XY: 636AN XY: 727240
GnomAD4 genome ? AF: 0.000696 AC: 106AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42AN XY: 74470
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:3
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | APOC2: PM2:Supporting, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 21, 2022 | This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 41 of the APOC2 protein (p.Lys41Thr). This variant is present in population databases (rs120074114, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of APOC2-related conditions (PMID: 1782747, 22135386, 24788417, 33111339). ClinVar contains an entry for this variant (Variation ID: 2581). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2023 | Observed in the heterozygous state in individuals with renal amyloidosis in published literature, but familial segregation data was not included in most cases (Sethi et al., 2018; Liapis et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22135386, 1782747, 30686043, 34426522, 31589614, 33395107, 30197986, 33111339) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Familial apolipoprotein C-II deficiency Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 31, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Feb 01, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Apolipoprotein c-ii variant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1991 | - - |
APOC2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 30, 2023 | The APOC2 c.122A>C variant is predicted to result in the amino acid substitution p.Lys41Thr. This variant was reported in individuals with apolipoprotein C2 deficiency/amyloidosis/hyperlipidemia (reported as p.Lys19Thr, Hegele et al. 1991. PubMed ID: 1782747; reported as p.K19T in Figure, Johansen et al. 2011. PubMed ID: 22135386; Sethi et al. 2018. PubMed ID: 30197986; Table S6, Marmontel. 2020. PubMed ID: 33111339). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as benign/uncertain/likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/2581/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 10, 2022 | The p.K41T variant (also known as c.122A>C), located in coding exon 2 of the APOC2 gene, results from an A to C substitution at nucleotide position 122. The lysine at codon 41 is replaced by threonine, an amino acid with similar properties. This variant (also referred to as Lys19Thr) has been detected in the heterozygous state in individuals with and without elevated triglycerides (Hegele RA et al. Dis Markers. 1991;9(2):73-80; Menke-Möllers I et al. Electrophoresis. 1992 Apr;13(4):244-51; Zysow BR et al. Clin Genet. 1994 Jun;45(6):292-7; Johansen CT et al. Circ Cardiovasc Genet. 2012 Feb;5(1):66-72). This variant has also been detected in some individuals with amyloidosis (Sethi S et al. Kidney Int Rep, 2018 Sep;3:1193-1201; Liapis K et al. Amyloid, 2019 Mar;26:52-53; Dasari S et al. Mayo Clin Proc, 2020 09;95:1852-1864). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at