Menu
GeneBe

rs7412

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_StrongBA1

The NM_000041.4(APOE):c.526C>T(p.Arg176Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0742 in 1,540,810 control chromosomes in the GnomAD database, including 4,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.078 ( 546 hom., cov: 32)
Exomes 𝑓: 0.074 ( 4063 hom. )

Consequence

APOE
NM_000041.4 missense

Scores

1
11
6

Clinical Significance

drug response reviewed by expert panel P:1U:1B:4O:4

Conservation

PhyloP100: 0.906
Variant links:
Genes affected
APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1
In a helix (size 31) in uniprot entity APOE_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_000041.4
BP4
Computational evidence support a benign effect (MetaRNN=0.0021114647).
BP6
Variant 19-44908822-C-T is Benign according to our data. Variant chr19-44908822-C-T is described in ClinVar as [drug_response]. Clinvar id is 17848.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {risk_factor=1, Benign=1, Likely_benign=1, other=1, drug_response=1}.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APOENM_000041.4 linkuse as main transcriptc.526C>T p.Arg176Cys missense_variant 4/4 ENST00000252486.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APOEENST00000252486.9 linkuse as main transcriptc.526C>T p.Arg176Cys missense_variant 4/41 NM_000041.4 P1
APOEENST00000425718.1 linkuse as main transcriptc.526C>T p.Arg176Cys missense_variant 3/31
APOEENST00000434152.5 linkuse as main transcriptc.604C>T p.Arg202Cys missense_variant 4/42
APOEENST00000446996.5 linkuse as main transcriptc.526C>T p.Arg176Cys missense_variant 4/42

Frequencies

GnomAD3 genomes
AF:
0.0779
AC:
11838
AN:
152004
Hom.:
546
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.105
Gnomad AMI
AF:
0.0121
Gnomad AMR
AF:
0.0419
Gnomad ASJ
AF:
0.0695
Gnomad EAS
AF:
0.0803
Gnomad SAS
AF:
0.0368
Gnomad FIN
AF:
0.0419
Gnomad MID
AF:
0.0446
Gnomad NFE
AF:
0.0795
Gnomad OTH
AF:
0.0761
GnomAD3 exomes
AF:
0.0615
AC:
8425
AN:
136984
Hom.:
315
AF XY:
0.0613
AC XY:
4615
AN XY:
75288
show subpopulations
Gnomad AFR exome
AF:
0.108
Gnomad AMR exome
AF:
0.0312
Gnomad ASJ exome
AF:
0.0797
Gnomad EAS exome
AF:
0.0742
Gnomad SAS exome
AF:
0.0419
Gnomad FIN exome
AF:
0.0454
Gnomad NFE exome
AF:
0.0751
Gnomad OTH exome
AF:
0.0608
GnomAD4 exome
AF:
0.0738
AC:
102550
AN:
1388698
Hom.:
4063
Cov.:
34
AF XY:
0.0726
AC XY:
49779
AN XY:
685974
show subpopulations
Gnomad4 AFR exome
AF:
0.107
Gnomad4 AMR exome
AF:
0.0319
Gnomad4 ASJ exome
AF:
0.0748
Gnomad4 EAS exome
AF:
0.0577
Gnomad4 SAS exome
AF:
0.0419
Gnomad4 FIN exome
AF:
0.0499
Gnomad4 NFE exome
AF:
0.0782
Gnomad4 OTH exome
AF:
0.0703
GnomAD4 genome
AF:
0.0778
AC:
11840
AN:
152112
Hom.:
546
Cov.:
32
AF XY:
0.0745
AC XY:
5538
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.104
Gnomad4 AMR
AF:
0.0419
Gnomad4 ASJ
AF:
0.0695
Gnomad4 EAS
AF:
0.0801
Gnomad4 SAS
AF:
0.0373
Gnomad4 FIN
AF:
0.0419
Gnomad4 NFE
AF:
0.0794
Gnomad4 OTH
AF:
0.0772
Alfa
AF:
0.0831
Hom.:
1411
Bravo
AF:
0.0781
TwinsUK
AF:
0.0917
AC:
340
ALSPAC
AF:
0.0924
AC:
356
ESP6500AA
AF:
0.0867
AC:
271
ESP6500EA
AF:
0.0562
AC:
356
ExAC
AF:
0.0360
AC:
3513
Asia WGS
AF:
0.0820
AC:
285
AN:
3460

ClinVar

Significance: drug response
Submissions summary: Pathogenic:1Uncertain:1Benign:4Other:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2Other:2
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
other, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 11, 2016- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2023APOE: PM5, BS1, BS2 -
risk factor, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute-- -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The APOE p.Arg176Cys variant, also known as the APOE ε2 allele, was identified in dbSNP (ID: rs7412), ClinVar (reported by EGL Genetics in relation to drug metabolism), Clinvitae, MutDB and LOVD 3.0. The variant was identified in control databases in 10996 of 168078 chromosomes (465 homozygous) at a frequency of 0.065422 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1632 of 15264 chromosomes (freq: 0.1069), Ashkenazi Jewish in 664 of 8410 chromosomes (freq: 0.07895), European (non-Finnish) in 5202 of 67810 chromosomes (freq: 0.07671), East Asian in 947 of 12608 chromosomes (freq: 0.07511), Other in 328 of 5174 chromosomes (freq: 0.06339), European (Finnish) in 472 of 10686 chromosomes (freq: 0.04417), South Asian in 947 of 22604 chromosomes (freq: 0.0419), and Latino in 804 of 25522 chromosomes (freq: 0.0315). Homozygous individuals with the APOE ε2 genotype are at a higher risk of developing type III hyperlipoproteinemia and mouse models with the APOE ε2 genotype develop a clear type III hyperlipoproteinemia phenotype (Breslow_1982_PMID: 7175379; Sullivan_1998_PMID: 9649566). However, this variant does not show full penetrance for type III hyperlipoproteinemia and other variants in conjunction with the APOE ε2 genotype have been suggested to contribute to the phenotype (Sakuma_2014_PMID: 24953047). Another study found that carriers of the APOE ε2 allele had lower baseline LDL cholesterol levels as well as a greater reduction of LDL-C from atorvastatin and pravastatin treatment compared to APOE ε4 carriers, implicating this variant as a pharmacogenetic variant (Meg_2009_PMID: 19667110). The p.Arg176 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Familial type 3 hyperlipoproteinemia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2005- -
not specified Benign:1
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Hypercholesterolemia Benign:1
Benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
atorvastatin response - Efficacy Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy
Warfarin response Other:1
drug response, no assertion criteria providedresearchPharmacogenomics Lab, Chungbuk National UniversityAug 31, 2010- likely responsive

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.17
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;T;.;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Benign
0.39
N
LIST_S2
Uncertain
0.93
D;D;D;D
MetaRNN
Benign
0.0021
T;T;T;T
MetaSVM
Benign
-0.60
T
MutationAssessor
Uncertain
2.3
M;.;.;.
MutationTaster
Benign
0.93
A
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.9
D;D;.;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.012
D;D;.;D
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.28
MPC
1.9
ClinPred
0.031
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.45
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7412; hg19: chr19-45412079; COSMIC: COSV52986153; COSMIC: COSV52986153; API