rs120074114

Positions:

• chr19-44948767-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000483.5(APOC2):​c.122A>C​(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:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (4 hom.)
• Consequence: APOC2 NM_000483.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:7 B:1
• Conservation: PhyloP100: 1.01

Genes affected

APOC2 (HGNC:609): (apolipoprotein C2) This gene encodes a lipid-binding protein belonging to the apolipoprotein gene family. The protein is secreted in plasma where it is a component of very low density lipoprotein. This protein activates the enzyme lipoprotein lipase, which hydrolyzes triglycerides and thus provides free fatty acids for cells. Mutations in this gene cause hyperlipoproteinemia type IB, characterized by hypertriglyceridemia, xanthomas, and increased risk of pancreatitis and early atherosclerosis. This gene is present in a cluster with other related apolipoprotein genes on chromosome 19. Naturally occurring read-through transcription exists between this gene and the neighboring upstream apolipoprotein C-IV (APOC4) gene. [provided by RefSeq, Mar 2011]

APOC4-APOC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01183328).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000696 (106/152304) while in subpopulation NFE AF= 0.00129 (88/68020). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 SD gene

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: 105 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000692 AC: 174 AN: 251452 Hom.: 0 AF XY: 0.000736 AC XY: 100 AN XY: 135896

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000878 AC: 1283 AN: 1461880 Hom.: 4 Cov.: 32 AF XY: 0.000875 AC XY: 636 AN XY: 727240

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74470

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000858

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000873 AC: 106

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain: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:2 Benign: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.012	T
MutationTaster	Benign	2.2e-11	A;A;A
Vest4		0.15
MVP		0.32
ClinPred		0.029	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs120074114; hg19: chr19-45452024; COSMIC: COSV52990513; COSMIC: COSV52990513;