chr2-21008652-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000384.3(APOB):c.8216C>T(p.Pro2739Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,613,762 control chromosomes in the GnomAD database, including 57,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2739Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 5077 hom., cov: 32)

Exomes 𝑓: 0.24 ( 52727 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:17

Conservation

PhyloP100: 10.0

Publications

162 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: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial hypobetalipoproteinemia 1
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.93353E-5).

BP6

Variant 2-21008652-G-A is Benign according to our data. Variant chr2-21008652-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.8216C>T	p.Pro2739Leu	missense	Exon 26 of 29	NP_000375.3	P04114

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.8216C>T	p.Pro2739Leu	missense	Exon 26 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

34945

AN:

151902

Hom.:

5077

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.732

Gnomad SAS

AF:

0.528

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.228

GnomAD2 exomes

AF:

0.293

AC:

73564

AN:

250888

AF XY:

0.301

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.258

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.725

Gnomad FIN exome

AF:

0.262

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.268

GnomAD4 exome

AF:

0.243

AC:

355716

AN:

1461742

Hom.:

52727

Cov.:

AF XY:

0.251

AC XY:

182548

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.143

AC:

4795

AN:

33468

American (AMR)

AF:

0.255

AC:

11388

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.193

AC:

5049

AN:

26132

East Asian (EAS)

AF:

0.731

AC:

29032

AN:

39698

South Asian (SAS)

AF:

0.495

AC:

42732

AN:

86248

European-Finnish (FIN)

AF:

0.266

AC:

14194

AN:

53412

Middle Eastern (MID)

AF:

0.317

AC:

1830

AN:

5768

European-Non Finnish (NFE)

AF:

0.208

AC:

230912

AN:

1111902

Other (OTH)

AF:

0.261

AC:

15784

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

17277

34554

51832

69109

86386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8336

16672

25008

33344

41680

<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:

0.230

AC:

34947

AN:

152020

Hom.:

5077

Cov.:

AF XY:

0.239

AC XY:

17756

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.151

AC:

6267

AN:

41478

American (AMR)

AF:

0.227

AC:

3469

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

655

AN:

3472

East Asian (EAS)

AF:

0.732

AC:

3775

AN:

5156

South Asian (SAS)

AF:

0.526

AC:

2534

AN:

4820

European-Finnish (FIN)

AF:

0.262

AC:

2772

AN:

10568

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.216

AC:

14689

AN:

67942

Other (OTH)

AF:

0.233

AC:

491

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1295

2590

3885

5180

6475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.226

Hom.:

21851

Bravo

AF:

0.221

TwinsUK

AF:

0.207

AC:

767

ALSPAC

AF:

0.204

AC:

787

ESP6500AA

AF:

0.158

AC:

694

ESP6500EA

AF:

0.217

AC:

1862

ExAC

AF:

0.293

AC:

35538

Asia WGS

AF:

0.595

AC:

2066

AN:

3478

EpiCase

AF:

0.225

EpiControl

AF:

0.216

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Familial hypercholesterolemia (3)

Hypercholesterolemia, familial, 1 (3)

Cardiovascular phenotype (1)

Familial hypobetalipoproteinemia 1 (1)

Hypercholesterolemia, autosomal dominant, type B (1)

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

Isolated systolic hypertension;C4021419:Triangular shaped proximal phalanx of the thumb;C5139433:Neutrophilia in presence of infection (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.000029

MetaSVM

Benign

-1.1

PhyloP100

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.72

MPC

0.27

ClinPred

0.037

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.92

Mutation Taster

=17/83

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over