2-21011100-T-C

Position:

chr2-21011100-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000384.3(APOB):c.5768A>G(p.His1923Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,614,200 control chromosomes in the GnomAD database, including 1,261 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1923Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 93 hom., cov: 33)

Exomes 𝑓: 0.037 ( 1168 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 8.02

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=0.0038963258).

BP6

Variant 2-21011100-T-C is Benign according to our data. Variant chr2-21011100-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21011100-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0286 (4353/152346) while in subpopulation NFE AF= 0.041 (2791/68030). AF 95% confidence interval is 0.0398. There are 93 homozygotes in gnomad4. There are 2232 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 93 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.5768A>G	p.His1923Arg	missense_variant	26/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.5768A>G	p.His1923Arg	missense_variant	26/29	1	NM_000384.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

4352

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00750

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0116

Gnomad ASJ

AF:

0.0262

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0403

Gnomad FIN

AF:

0.0661

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0410

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0314

AC:

7901

AN:

251320

Hom.:

190

AF XY:

0.0320

AC XY:

4347

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.00917

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0371

Gnomad FIN exome

AF:

0.0675

Gnomad NFE exome

AF:

0.0389

Gnomad OTH exome

AF:

0.0331

GnomAD4 exome

AF:

0.0366

AC:

53503

AN:

1461854

Hom.:

1168

Cov.:

AF XY:

0.0367

AC XY:

26707

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00502

Gnomad4 AMR exome

AF:

0.00995

Gnomad4 ASJ exome

AF:

0.0260

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0370

Gnomad4 FIN exome

AF:

0.0661

Gnomad4 NFE exome

AF:

0.0390

Gnomad4 OTH exome

AF:

0.0315

GnomAD4 genome

AF:

0.0286

AC:

4353

AN:

152346

Hom.:

Cov.:

AF XY:

0.0300

AC XY:

2232

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00748

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.0262

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0408

Gnomad4 FIN

AF:

0.0661

Gnomad4 NFE

AF:

0.0410

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0354

Hom.:

226

Bravo

AF:

0.0232

TwinsUK

AF:

0.0434

AC:

161

ALSPAC

AF:

0.0464

AC:

179

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0376

AC:

323

ExAC

AF:

0.0312

AC:

3783

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0387

EpiControl

AF:

0.0355

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 11, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypercholesterolemia, familial, 1

Benign:3

Likely benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	4/101 non-FH individuals -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -

Familial hypercholesterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 21, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 25, 2017	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 09, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.35

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0040

Vest4

0.52

MPC

0.29

ClinPred

0.016

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.80

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