2-21043879-CCAG-CCAGCAGCAG

Position:

chr2-21043879-CCAG-CCAGCAGCAG

Variant summary

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

The ENST00000233242.5(APOB):c.66_67insCTGCTG(p.Leu21_Leu22dup) variant causes a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L22L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00062 ( 17 hom. )

Consequence

APOB
ENST00000233242.5 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]

APOB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000233242.5.

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/exons	MANE	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.66_67insCTGCTG	p.Leu21_Leu22dup	inframe_insertion	1/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
APOB	ENST00000233242.5 linkuse as main transcript	c.66_67insCTGCTG	p.Leu21_Leu22dup	inframe_insertion	1/29	1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000399256.4 linkuse as main transcript	c.66_67insCTGCTG	p.Leu21_Leu22dup	inframe_insertion	1/17	1		ENSP00000382200
APOB	ENST00000673739.2 linkuse as main transcript	c.66_67insCTGCTG	p.Leu21_Leu22dup	inframe_insertion, NMD_transcript_variant	1/25			ENSP00000501110
APOB	ENST00000673882.2 linkuse as main transcript	c.66_67insCTGCTG	p.Leu21_Leu22dup	inframe_insertion, NMD_transcript_variant	1/23			ENSP00000501253

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

200

AN:

150590

Hom.:

Cov.:

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.:

AF XY:

0.00191

AC XY:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.00134

AC XY:

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

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	APOB: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2023	- -

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

APOB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2018

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

Benign, criteria provided, single submitter

clinical testing

GENinCode PLC

Sep 27, 2023

- -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over