2-21010226-CTCA-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_SupportingBP6BS2

The NM_000384.3(APOB):​c.6639_6641delTGA​(p.Asp2213del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,561,718 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D2213D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0041 ( 40 hom. )

Consequence

APOB
NM_000384.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:15

Conservation

PhyloP100: 2.98

Publications

2 publications found
Variant links:
Genes affected
APOB (HGNC:603): (apolipoprotein B) This gene product is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL), and is the ligand for the LDL receptor. It occurs in plasma as two main isoforms, apoB-48 and apoB-100: the former is synthesized exclusively in the gut and the latter in the liver. The intestinal and the hepatic forms of apoB are encoded by a single gene from a single, very long mRNA. The two isoforms share a common N-terminal sequence. The shorter apoB-48 protein is produced after RNA editing of the apoB-100 transcript at residue 2180 (CAA->UAA), resulting in the creation of a stop codon, and early translation termination. Mutations in this gene or its regulatory region cause hypobetalipoproteinemia, normotriglyceridemic hypobetalipoproteinemia, and hypercholesterolemia due to ligand-defective apoB, diseases affecting plasma cholesterol and apoB levels. [provided by RefSeq, Dec 2019]
APOB Gene-Disease associations (from GenCC):
  • hypercholesterolemia, autosomal dominant, type B
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
  • familial hypobetalipoproteinemia 1
    Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
  • homozygous familial hypercholesterolemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_000384.3. Strenght limited to Supporting due to length of the change: 1aa.
BP6
Variant 2-21010226-CTCA-C is Benign according to our data. Variant chr2-21010226-CTCA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180280.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR,SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APOBNM_000384.3 linkc.6639_6641delTGA p.Asp2213del disruptive_inframe_deletion Exon 26 of 29 ENST00000233242.5 NP_000375.3 P04114Q7Z7Q0Q59HB3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOBENST00000233242.5 linkc.6639_6641delTGA p.Asp2213del disruptive_inframe_deletion Exon 26 of 29 1 NM_000384.3 ENSP00000233242.1 P04114

Frequencies

GnomAD3 genomes
AF:
0.00416
AC:
633
AN:
152144
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000652
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000982
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00228
Gnomad FIN
AF:
0.0170
Gnomad MID
AF:
0.00318
Gnomad NFE
AF:
0.00573
Gnomad OTH
AF:
0.00335
GnomAD2 exomes
AF:
0.00490
AC:
1069
AN:
217994
AF XY:
0.00508
show subpopulations
Gnomad AFR exome
AF:
0.000333
Gnomad AMR exome
AF:
0.000998
Gnomad ASJ exome
AF:
0.000872
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0190
Gnomad NFE exome
AF:
0.00583
Gnomad OTH exome
AF:
0.00601
GnomAD4 exome
AF:
0.00408
AC:
5752
AN:
1409456
Hom.:
40
AF XY:
0.00401
AC XY:
2795
AN XY:
696196
show subpopulations
African (AFR)
AF:
0.000353
AC:
11
AN:
31170
American (AMR)
AF:
0.00121
AC:
44
AN:
36260
Ashkenazi Jewish (ASJ)
AF:
0.00136
AC:
33
AN:
24290
East Asian (EAS)
AF:
0.0000256
AC:
1
AN:
38994
South Asian (SAS)
AF:
0.00181
AC:
142
AN:
78434
European-Finnish (FIN)
AF:
0.0191
AC:
947
AN:
49614
Middle Eastern (MID)
AF:
0.000182
AC:
1
AN:
5492
European-Non Finnish (NFE)
AF:
0.00402
AC:
4372
AN:
1087144
Other (OTH)
AF:
0.00346
AC:
201
AN:
58058
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.449
Heterozygous variant carriers
0
253
507
760
1014
1267
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
136
272
408
544
680
<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:
0.00416
AC:
633
AN:
152262
Hom.:
2
Cov.:
33
AF XY:
0.00442
AC XY:
329
AN XY:
74446
show subpopulations
African (AFR)
AF:
0.000650
AC:
27
AN:
41556
American (AMR)
AF:
0.000981
AC:
15
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.000577
AC:
2
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00228
AC:
11
AN:
4822
European-Finnish (FIN)
AF:
0.0170
AC:
180
AN:
10604
Middle Eastern (MID)
AF:
0.00342
AC:
1
AN:
292
European-Non Finnish (NFE)
AF:
0.00573
AC:
390
AN:
68014
Other (OTH)
AF:
0.00332
AC:
7
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
35
70
104
139
174
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00525
Hom.:
0
Bravo
AF:
0.00251

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:15
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:4Benign:3
Mar 01, 2016
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 07, 2014
Blueprint Genetics
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 02, 2018
Robarts Research Institute, Western University
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 01, 2016
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

1/96 normolipidaemic Portuguese controls -

-
Institute for Integrative and Experimental Genomics, University of Luebeck
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:research

- -

Mar 01, 2016
Iberoamerican FH Network
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

not provided Benign:4
Dec 07, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

APOB: PM4:Supporting, BS2 -

Sep 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 31, 2019
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27153395, 9050776, 24234650, 23680767, 33111339) -

not specified Benign:2
Mar 28, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.9% (122/6498) Finnish chromosomes -

Jul 06, 2017
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial hypercholesterolemia Benign:2
Mar 07, 2018
Color Diagnostics, LLC DBA Color Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 19, 2023
GENinCode PLC
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hypercholesterolemia, autosomal dominant, type B Benign:1
Jan 01, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

APOB-related disorder Benign:1
Nov 14, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1
May 09, 2017
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
PhyloP100
3.0
Mutation Taster
=43/57
disease causing

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

Other links and lift over

dbSNP: rs541497967; hg19: chr2-21233098; API