chr2-21011127-T-C

Position:

chr2-21011127-T-C

Variant summary

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

The ENST00000233242.5(APOB):c.5741A>G(p.Asn1914Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0191 in 1,614,218 control chromosomes in the GnomAD database, including 424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. N1914N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 48 hom., cov: 33)

Exomes 𝑓: 0.019 ( 376 hom. )

Consequence

APOB
ENST00000233242.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.20

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=0.0053982735).

BP6

Variant 2-21011127-T-C is Benign according to our data. Variant chr2-21011127-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 218447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21011127-T-C is described in Lovd as [Benign]. Variant chr2-21011127-T-C is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.5741A>G	p.Asn1914Ser	missense_variant	26/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.5741A>G	p.Asn1914Ser	missense_variant	26/29	1	NM_000384.3	ENSP00000233242	P1

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2576

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0440

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.0279

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0224

AC:

5636

AN:

251360

Hom.:

126

AF XY:

0.0210

AC XY:

2847

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.0659

Gnomad ASJ exome

AF:

0.0157

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00598

Gnomad FIN exome

AF:

0.0274

Gnomad NFE exome

AF:

0.0193

Gnomad OTH exome

AF:

0.0245

GnomAD4 exome

AF:

0.0193

AC:

28185

AN:

1461870

Hom.:

376

Cov.:

AF XY:

0.0188

AC XY:

13674

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.0627

Gnomad4 ASJ exome

AF:

0.0162

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00612

Gnomad4 FIN exome

AF:

0.0284

Gnomad4 NFE exome

AF:

0.0195

Gnomad4 OTH exome

AF:

0.0177

GnomAD4 genome

AF:

0.0170

AC:

2583

AN:

152348

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1283

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00491

Gnomad4 AMR

AF:

0.0445

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00539

Gnomad4 FIN

AF:

0.0279

Gnomad4 NFE

AF:

0.0188

Gnomad4 OTH

AF:

0.0165

Alfa

AF:

0.0183

Hom.:

Bravo

AF:

0.0185

TwinsUK

AF:

0.0259

AC:

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0180

AC:

155

ExAC

AF:

0.0201

AC:

2445

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0234

EpiControl

AF:

0.0197

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 34/2178=1.5% -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2016	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:5

Likely benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 27, 2017	- -
Likely benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	2/101 non-FH individuals -
Benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 22, 2022	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 09, 2018

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. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2015

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. -

Familial hypercholesterolemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

GENinCode PLC

Jun 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.97

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.43

MutationTaster

Benign

0.63

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.19

Sift

Uncertain

0.013

Sift4G

Uncertain

0.0060

Vest4

0.29

MPC

0.046

ClinPred

0.033

GERP RS

5.7

gMVP

0.35

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