2-21003346-GAAA-GAAAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000384.3(APOB):c.12088-13dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,091,966 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)

Exomes 𝑓: 0.033 ( 3 hom. )

Consequence

APOB
NM_000384.3 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.342

Publications

1 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

APOB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 2-21003346-G-GA is Benign according to our data. Variant chr2-21003346-G-GA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334083.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.12088-13dupT		intron_variant	Intron 28 of 28	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 link	c.12088-13_12088-12insT		intron_variant	Intron 28 of 28	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

142

AN:

137534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000695

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000724

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00249

Gnomad SAS

AF:

0.0163

Gnomad FIN

AF:

0.000127

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000318

Gnomad OTH

AF:

0.000526

GnomAD2 exomes

AF:

0.0126

AC:

1788

AN:

141744

AF XY:

0.0137

show subpopulations

Gnomad AFR exome

AF:

0.00547

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.00669

Gnomad FIN exome

AF:

0.0236

Gnomad NFE exome

AF:

0.00695

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.0327

AC:

31172

AN:

954370

Hom.:

Cov.:

AF XY:

0.0317

AC XY:

14969

AN XY:

471794

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0293

AC:

609

AN:

20820

American (AMR)

AF:

0.0132

AC:

356

AN:

26966

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

318

AN:

14948

East Asian (EAS)

AF:

0.0151

AC:

370

AN:

24470

South Asian (SAS)

AF:

0.0438

AC:

2272

AN:

51848

European-Finnish (FIN)

AF:

0.0197

AC:

614

AN:

31240

Middle Eastern (MID)

AF:

0.0178

AC:

AN:

4104

European-Non Finnish (NFE)

AF:

0.0342

AC:

25359

AN:

742168

Other (OTH)

AF:

0.0318

AC:

1201

AN:

37806

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.255

Heterozygous variant carriers

4466

8932

13397

17863

22329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1176

2352

3528

4704

5880

<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:

0.00104

AC:

143

AN:

137596

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

AN XY:

66416

show subpopulations

African (AFR)

AF:

0.000720

AC:

AN:

37502

American (AMR)

AF:

0.000723

AC:

AN:

13840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3250

East Asian (EAS)

AF:

0.00249

AC:

AN:

4812

South Asian (SAS)

AF:

0.0164

AC:

AN:

4392

European-Finnish (FIN)

AF:

0.000127

AC:

AN:

7858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000318

AC:

AN:

62918

Other (OTH)

AF:

0.000521

AC:

AN:

1920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0395

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypobetalipoproteinemia

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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