2-21001981-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000384.3(APOB):c.13441G>A(p.Ala4481Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,613,902 control chromosomes in the GnomAD database, including 969 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A4481A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 102 hom., cov: 32)

Exomes 𝑓: 0.032 ( 867 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: 0.190

Publications

32 publications found

Variant links:

COSMIC-nc: COSV107232167

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020777583).

BP6

Variant 2-21001981-C-T is Benign according to our data. Variant chr2-21001981-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128419.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.13441G>A	p.Ala4481Thr	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.13441G>A	p.Ala4481Thr	missense_variant	Exon 29 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.0260

AC:

3958

AN:

152084

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00623

Gnomad AMI

AF:

0.0802

Gnomad AMR

AF:

0.0406

Gnomad ASJ

AF:

0.0366

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.0238

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0359

Gnomad OTH

AF:

0.0326

GnomAD2 exomes

AF:

0.0252

AC:

6310

AN:

250316

AF XY:

0.0262

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0358

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0209

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0286

GnomAD4 exome

AF:

0.0317

AC:

46356

AN:

1461698

Hom.:

867

Cov.:

AF XY:

0.0317

AC XY:

23064

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.00624

AC:

209

AN:

33468

American (AMR)

AF:

0.0195

AC:

872

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0352

AC:

919

AN:

26130

East Asian (EAS)

AF:

0.000126

AC:

AN:

39682

South Asian (SAS)

AF:

0.0206

AC:

1774

AN:

86254

European-Finnish (FIN)

AF:

0.0215

AC:

1146

AN:

53348

Middle Eastern (MID)

AF:

0.0614

AC:

354

AN:

5768

European-Non Finnish (NFE)

AF:

0.0354

AC:

39341

AN:

1111940

Other (OTH)

AF:

0.0287

AC:

1736

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2624

5248

7872

10496

13120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1440

2880

4320

5760

7200

<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:

0.0260

AC:

3957

AN:

152204

Hom.:

102

Cov.:

AF XY:

0.0259

AC XY:

1930

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00621

AC:

258

AN:

41526

American (AMR)

AF:

0.0406

AC:

621

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0366

AC:

127

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0205

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0238

AC:

252

AN:

10596

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0359

AC:

2442

AN:

68010

Other (OTH)

AF:

0.0322

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

197

393

590

786

983

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0321

Hom.:

257

Bravo

AF:

0.0255

TwinsUK

AF:

0.0353

AC:

131

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0397

AC:

341

ExAC

AF:

0.0240

AC:

2914

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0427

EpiControl

AF:

0.0386

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 18, 2022

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 22, 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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypercholesterolemia, familial, 1

Uncertain:2Benign:1

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 17, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Benign:2

Oct 16, 2024

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BA1 -

Aug 04, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

May 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 08, 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

0.092

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.3

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.41

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

PhyloP100

0.19

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

REVEL

Benign

0.033

Sift

Benign

0.15

Sift4G

Benign

0.13

Vest4

0.020

MPC

0.036

ClinPred

0.0043

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.094

Mutation Taster

=89/11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over