rs5126

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000483.5(APOC2):c.229A>C(p.Lys77Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,613,756 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K77R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0072 ( 15 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 16 hom. )

Consequence

APOC2
NM_000483.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 0.0760

Publications

24 publications found

Variant links:

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]

APOC2 links:

APOC4-APOC2 (HGNC:44426): (APOC4-APOC2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring apolipoprotein C-IV (APOC4) and apolipoprotein C-II (APOC2) genes on chromosome 19. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

APOC4-APOC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037645698).

BP6

Variant 19-44949172-A-C is Benign according to our data. Variant chr19-44949172-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00723 (1099/152082) while in subpopulation AFR AF = 0.0254 (1052/41458). AF 95% confidence interval is 0.0241. There are 15 homozygotes in GnomAd4. There are 513 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOC2	NM_000483.5 link	c.229A>C	p.Lys77Gln	missense_variant	Exon 4 of 4	ENST00000252490.7	NP_000474.2
APOC4-APOC2	NR_037932.1 link	n.1436A>C		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOC2	ENST00000252490.7 link	c.229A>C	p.Lys77Gln	missense_variant	Exon 4 of 4	2	NM_000483.5	ENSP00000252490.5
APOC4-APOC2	ENST00000589057.5 link	c.460A>C	p.Lys154Gln	missense_variant	Exon 5 of 5	5		ENSP00000468139.1

Frequencies

GnomAD3 genomes

AF:

0.00722

AC:

1097

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00183

AC:

459

AN:

251064

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.0261

Gnomad AMR exome

AF:

0.000812

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000755

AC:

1104

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000640

AC XY:

465

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0273

AC:

914

AN:

33468

American (AMR)

AF:

0.000940

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000186

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111948

Other (OTH)

AF:

0.00171

AC:

103

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

114

170

227

284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00723

AC:

1099

AN:

152082

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

513

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0254

AC:

1052

AN:

41458

American (AMR)

AF:

0.00203

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

67990

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00825

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00231

AC:

280

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial apolipoprotein C-II deficiency

Benign:3

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

NM_000483.4:c.229A>C in the APOC2 gene has an allele frequency of 0.026 in African subpopulation in the gnomAD database, including 8 homozygous occurrences. Pathogenic computational verdict because pathogenic predictions from DANN, MutationAssessor, MutationTaster and SIFTT. aken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2. -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 03, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31589614, 33111339) -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

APOLIPOPROTEIN C-II (AFRICAN)

Pathogenic:1

Feb 01, 1986

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:1

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.063, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Cardiovascular phenotype

Benign:1

Aug 26, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;T;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.64

T;T;T;.

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.3

.;M;.;M

PhyloP100

0.076

PROVEAN

Uncertain

-2.7

.;D;.;.

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Benign

0.063

T;T;D;T

Polyphen

0.66

.;P;.;P

Vest4

0.16

MVP

0.47

MPC

0.77

ClinPred

0.073

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.69

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over