2-21043879-CCAGCAGCAG-CCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_000384.3(APOB):​c.61_66dupCTGCTG​(p.Leu21_Leu22dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,416,518 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 31)
Exomes 𝑓: 0.00062 ( 17 hom. )

Consequence

APOB
NM_000384.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.29
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_000384.3.
BP6
Variant 2-21043879-C-CCAGCAG is Benign according to our data. Variant chr2-21043879-C-CCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 426250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000621 (786/1265826) while in subpopulation AMR AF= 0.0243 (716/29458). AF 95% confidence interval is 0.0228. There are 17 homozygotes in gnomad4_exome. There are 318 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APOBNM_000384.3 linkc.61_66dupCTGCTG p.Leu21_Leu22dup conservative_inframe_insertion Exon 1 of 29 ENST00000233242.5 NP_000375.3 P04114Q7Z7Q0Q59HB3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOBENST00000233242.5 linkc.61_66dupCTGCTG p.Leu21_Leu22dup conservative_inframe_insertion Exon 1 of 29 1 NM_000384.3 ENSP00000233242.1 P04114
APOBENST00000399256.4 linkc.61_66dupCTGCTG p.Leu21_Leu22dup conservative_inframe_insertion Exon 1 of 17 1 ENSP00000382200.4 A8MUN2
APOBENST00000673739.2 linkn.61_66dupCTGCTG non_coding_transcript_exon_variant Exon 1 of 25 ENSP00000501110.2 A0A669KB70
APOBENST00000673882.2 linkn.61_66dupCTGCTG non_coding_transcript_exon_variant Exon 1 of 23 ENSP00000501253.2 A0A669KB70

Frequencies

GnomAD3 genomes
AF:
0.00133
AC:
200
AN:
150590
Hom.:
2
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000850
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0102
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000195
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000890
Gnomad OTH
AF:
0.00145
GnomAD3 exomes
AF:
0.00337
AC:
248
AN:
73646
Hom.:
2
AF XY:
0.00191
AC XY:
80
AN XY:
41836
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0171
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00274
GnomAD4 exome
AF:
0.000621
AC:
786
AN:
1265826
Hom.:
17
Cov.:
31
AF XY:
0.000509
AC XY:
318
AN XY:
624992
show subpopulations
Gnomad4 AFR exome
AF:
0.000383
Gnomad4 AMR exome
AF:
0.0243
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000281
Gnomad4 OTH exome
AF:
0.000588
GnomAD4 genome
AF:
0.00132
AC:
199
AN:
150692
Hom.:
2
Cov.:
31
AF XY:
0.00134
AC XY:
99
AN XY:
73630
show subpopulations
Gnomad4 AFR
AF:
0.000848
Gnomad4 AMR
AF:
0.0101
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000195
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000890
Gnomad4 OTH
AF:
0.00143

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Nov 09, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 23, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 22, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

APOB: BS1, BS2 -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

APOB-related disorder Benign:1
Mar 19, 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
Sep 30, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Familial hypercholesterolemia Benign:1
Sep 27, 2023
GENinCode PLC
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs745520533; hg19: chr2-21266751; API