chr2-21003346-GA-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000384.3(APOB):c.12088-13delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,174,020 control chromosomes in the GnomAD database, including 31 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 5 hom., cov: 32)

Exomes 𝑓: 0.013 ( 26 hom. )

Consequence

APOB
NM_000384.3 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.342

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 was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 2-21003346-GA-G is Benign according to our data. Variant chr2-21003346-GA-G is described in ClinVar as [Benign]. Clinvar id is 490382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21003346-GA-G is described in Lovd as [Benign]. Variant chr2-21003346-GA-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00358 (493/137590) while in subpopulation EAS AF = 0.0426 (205/4808). AF 95% confidence interval is 0.0379. There are 5 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,SD,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.12088-13delT		intron_variant	Intron 28 of 28	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 link	c.12088-13delT		intron_variant	Intron 28 of 28	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.00357

AC:

491

AN:

137524

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00232

Gnomad ASJ

AF:

0.00646

Gnomad EAS

AF:

0.0425

Gnomad SAS

AF:

0.00272

Gnomad FIN

AF:

0.000509

Gnomad MID

AF:

0.0105

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.00789

GnomAD2 exomes

AF:

0.0184

AC:

2615

AN:

141744

AF XY:

0.0180

show subpopulations

Gnomad AFR exome

AF:

0.00527

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.0266

Gnomad EAS exome

AF:

0.0830

Gnomad FIN exome

AF:

0.0182

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.0214

GnomAD4 exome

AF:

0.0134

AC:

13904

AN:

1036430

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

6722

AN XY:

513868

show subpopulations

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

African (AFR)

AF:

0.0128

AC:

293

AN:

22828

American (AMR)

AF:

0.0107

AC:

316

AN:

29532

Ashkenazi Jewish (ASJ)

AF:

0.0148

AC:

254

AN:

17156

East Asian (EAS)

AF:

0.0540

AC:

1491

AN:

27616

South Asian (SAS)

AF:

0.0116

AC:

676

AN:

58098

European-Finnish (FIN)

AF:

0.0116

AC:

393

AN:

33870

Middle Eastern (MID)

AF:

0.0133

AC:

AN:

4374

European-Non Finnish (NFE)

AF:

0.0122

AC:

9747

AN:

801148

Other (OTH)

AF:

0.0162

AC:

676

AN:

41808

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.319

Heterozygous variant carriers

1564

3127

4691

6254

7818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00358

AC:

493

AN:

137590

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

252

AN XY:

66410

show subpopulations

African (AFR)

AF:

0.00245

AC:

AN:

37500

American (AMR)

AF:

0.00231

AC:

AN:

13834

Ashkenazi Jewish (ASJ)

AF:

0.00646

AC:

AN:

3250

East Asian (EAS)

AF:

0.0426

AC:

205

AN:

4808

South Asian (SAS)

AF:

0.00273

AC:

AN:

4390

European-Finnish (FIN)

AF:

0.000509

AC:

AN:

7852

Middle Eastern (MID)

AF:

0.0150

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00172

AC:

108

AN:

62934

Other (OTH)

AF:

0.00782

AC:

AN:

1918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0251

Hom.:

Bravo

AF:

0.00370

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Hypercholesterolemia, familial, 1

Benign:1

Aug 28, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

LitVar

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

chr2-21003346-GA-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over