chr2-21009253-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000384.3(APOB):c.7615G>A(p.Val2539Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,070 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 9 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:9

Conservation

PhyloP100: 0.00500

Publications

6 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036623776).

BP6

Variant 2-21009253-C-T is Benign according to our data. Variant chr2-21009253-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334125.

BS2

High Homozygotes in GnomAdExome4 at 9 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.7615G>A	p.Val2539Ile	missense_variant	Exon 26 of 29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 link	c.7615G>A	p.Val2539Ile	missense_variant	Exon 26 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

317

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00325

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00235

AC:

591

AN:

251156

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00472

Gnomad NFE exome

AF:

0.00332

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00300

AC:

4392

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

2211

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33470

American (AMR)

AF:

0.000134

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00320

AC:

276

AN:

86254

European-Finnish (FIN)

AF:

0.00395

AC:

211

AN:

53408

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00336

AC:

3731

AN:

1111930

Other (OTH)

AF:

0.00233

AC:

141

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

274

547

821

1094

1368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.00208

AC:

317

AN:

152312

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41570

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00228

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00556

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00325

AC:

221

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00261

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00240

AC:

291

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00255

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B

Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Aug 01, 2017

Phosphorus, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypobetalipoproteinemia 1

Uncertain:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2017

Phosphorus, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Sep 20, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypercholesterolemia, familial, 1

Benign:2

Jun 26, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 22, 2019

Robarts Research Institute, Western University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

APOB: BP4 -

May 18, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

APOB-related disorder

Benign:1

Mar 18, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Oct 30, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.7

(source)

DANN

Benign

0.93

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.30

M_CAP

Benign

0.0054

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.93

PhyloP100

0.0050

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.32

REVEL

Benign

0.041

Sift

Benign

0.27

Sift4G

Benign

0.33

Vest4

0.029

MVP

0.37

MPC

0.033

ClinPred

0.00091

GERP RS

-0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.23

Mutation Taster

=98/2

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over