2-21005955-C-T

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.10913G>A(p.Arg3638Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0841 in 1,613,688 control chromosomes in the GnomAD database, including 6,499 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict 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. R3638W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.066 ( 458 hom., cov: 32)

Exomes 𝑓: 0.086 ( 6041 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:18

Conservation

PhyloP100: 3.08

Publications

66 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017217398).

BP6

Variant 2-21005955-C-T is Benign according to our data. Variant chr2-21005955-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0967 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.10913G>A	p.Arg3638Gln	missense	Exon 26 of 29	NP_000375.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.10913G>A	p.Arg3638Gln	missense	Exon 26 of 29	ENSP00000233242.1

Frequencies

GnomAD3 genomes

AF:

0.0655

AC:

9961

AN:

152046

Hom.:

456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0235

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.0536

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.0693

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0921

Gnomad OTH

AF:

0.0633

GnomAD2 exomes

AF:

0.0700

AC:

17541

AN:

250484

AF XY:

0.0686

show subpopulations

Gnomad AFR exome

AF:

0.0209

Gnomad AMR exome

AF:

0.0989

Gnomad ASJ exome

AF:

0.0502

Gnomad EAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.0715

Gnomad NFE exome

AF:

0.0924

Gnomad OTH exome

AF:

0.0788

GnomAD4 exome

AF:

0.0861

AC:

125770

AN:

1461524

Hom.:

6041

Cov.:

AF XY:

0.0838

AC XY:

60930

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.0179

AC:

599

AN:

33466

American (AMR)

AF:

0.0977

AC:

4362

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.0517

AC:

1351

AN:

26132

East Asian (EAS)

AF:

0.000227

AC:

AN:

39696

South Asian (SAS)

AF:

0.0264

AC:

2275

AN:

86236

European-Finnish (FIN)

AF:

0.0785

AC:

4188

AN:

53380

Middle Eastern (MID)

AF:

0.0470

AC:

271

AN:

5766

European-Non Finnish (NFE)

AF:

0.0972

AC:

108116

AN:

1111836

Other (OTH)

AF:

0.0762

AC:

4599

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

6921

13842

20762

27683

34604

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3884

7768

11652

15536

19420

<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:

0.0655

AC:

9968

AN:

152164

Hom.:

458

Cov.:

AF XY:

0.0635

AC XY:

4723

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0234

AC:

973

AN:

41514

American (AMR)

AF:

0.101

AC:

1542

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0536

AC:

186

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5178

South Asian (SAS)

AF:

0.0228

AC:

110

AN:

4814

European-Finnish (FIN)

AF:

0.0693

AC:

734

AN:

10598

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0920

AC:

6259

AN:

67998

Other (OTH)

AF:

0.0632

AC:

133

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

464

927

1391

1854

2318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0822

Hom.:

2878

Bravo

AF:

0.0670

TwinsUK

AF:

0.107

AC:

395

ALSPAC

AF:

0.106

AC:

410

ESP6500AA

AF:

0.0225

AC:

ESP6500EA

AF:

0.0898

AC:

772

ExAC

AF:

0.0686

AC:

8330

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0943

EpiControl

AF:

0.0895

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Familial hypercholesterolemia (3)

Hypercholesterolemia, familial, 1 (2)

not provided (2)

Cardiovascular phenotype (1)

Familial hypobetalipoproteinemia 1 (1)

Hypercholesterolemia, autosomal dominant, type B (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.61

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.15

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

PhyloP100

3.1

PrimateAI

Benign

0.18

PROVEAN

Benign

1.4

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.051

MPC

0.040

ClinPred

0.0068

GERP RS

3.2

gMVP

0.20

Mutation Taster

=99/1

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over