rs120074114
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
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 -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APOC2 | NM_000483.5 | c.122A>C | p.Lys41Thr | missense_variant | Exon 3 of 4 | ENST00000252490.7 | NP_000474.2 | |
APOC4-APOC2 | NR_037932.1 | n.1329A>C | non_coding_transcript_exon_variant | Exon 5 of 6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APOC2 | ENST00000252490.7 | c.122A>C | p.Lys41Thr | missense_variant | Exon 3 of 4 | 2 | NM_000483.5 | ENSP00000252490.5 | ||
APOC4-APOC2 | ENST00000589057.5 | c.353A>C | p.Lys118Thr | missense_variant | Exon 4 of 5 | 5 | ENSP00000468139.1 |
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:4
BS1 -
Observed in the heterozygous state in individuals with renal amyloidosis, dyslipidemia, and acute myocardial infaraction (AMI) in published literature (PMID: 33111339, 30197986, 30686043, 36555767, 36325899); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22135386, 1782747, 30686043, 34426522, 31589614, 33111339, 30197986, 36555767, 33395107, 36325899) -
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APOC2: PM2:Supporting, BP4 -
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. -
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Familial apolipoprotein C-II deficiency Uncertain:3Benign:1
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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. -
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Apolipoprotein c-ii variant Pathogenic:1
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APOC2-related disorder Uncertain:1
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 Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at