2-21002613-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000384.3(APOB):c.12809G>C(p.Arg4270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,613,894 control chromosomes in the GnomAD database, including 1,665 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.054 ( 394 hom., cov: 32)

Exomes 𝑓: 0.028 ( 1271 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.137

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 made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015838444).

BP6

Variant 2-21002613-C-G is Benign according to our data. Variant chr2-21002613-C-G is described in ClinVar as [Benign]. Clinvar id is 255977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21002613-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.12809G>C	p.Arg4270Thr	missense_variant	Exon 29 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.12809G>C	p.Arg4270Thr	missense_variant	Exon 29 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.0538

AC:

8187

AN:

152068

Hom.:

388

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.0616

Gnomad EAS

AF:

0.0318

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.0355

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0535

GnomAD3 exomes

AF:

0.0496

AC:

12448

AN:

251068

Hom.:

702

AF XY:

0.0414

AC XY:

5624

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.167

Gnomad ASJ exome

AF:

0.0611

Gnomad EAS exome

AF:

0.0291

Gnomad SAS exome

AF:

0.0138

Gnomad FIN exome

AF:

0.0371

Gnomad NFE exome

AF:

0.0204

Gnomad OTH exome

AF:

0.0417

GnomAD4 exome

AF:

0.0277

AC:

40532

AN:

1461708

Hom.:

1271

Cov.:

AF XY:

0.0264

AC XY:

19231

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.108

Gnomad4 AMR exome

AF:

0.162

Gnomad4 ASJ exome

AF:

0.0620

Gnomad4 EAS exome

AF:

0.0372

Gnomad4 SAS exome

AF:

0.0133

Gnomad4 FIN exome

AF:

0.0367

Gnomad4 NFE exome

AF:

0.0192

Gnomad4 OTH exome

AF:

0.0344

GnomAD4 genome

AF:

0.0540

AC:

8220

AN:

152186

Hom.:

394

Cov.:

AF XY:

0.0546

AC XY:

4060

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.104

Gnomad4 AMR

AF:

0.103

Gnomad4 ASJ

AF:

0.0616

Gnomad4 EAS

AF:

0.0319

Gnomad4 SAS

AF:

0.0156

Gnomad4 FIN

AF:

0.0355

Gnomad4 NFE

AF:

0.0197

Gnomad4 OTH

AF:

0.0549

Alfa

AF:

0.0236

Hom.:

Bravo

AF:

0.0656

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.104

AC:

460

ESP6500EA

AF:

0.0209

AC:

180

ExAC

AF:

0.0456

AC:

5538

Asia WGS

AF:

0.0400

AC:

137

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Dec 01, 2016

GeneDx

Significance: 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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1

Benign:4

Jun 27, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 22, 2019

Robarts Research Institute, Western University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Benign:2

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial hypercholesterolemia

Benign:2

Aug 24, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2023

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial hypobetalipoproteinemia 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype

Benign:1

Dec 16, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

0.16

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

4.9

DANN

Benign

0.50

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.41

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.7

REVEL

Benign

0.017

Sift

Benign

0.10

Sift4G

Uncertain

0.049

Vest4

0.15

MPC

0.049

ClinPred

0.0039

GERP RS

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.46

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over