2-21006807-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000384.3(APOB):c.10061C>G(p.Ala3354Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,614,068 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.0025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.845

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068757534).

BP6

Variant 2-21006807-G-C is Benign according to our data. Variant chr2-21006807-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 369882.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.10061C>G	p.Ala3354Gly	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.10061C>G	p.Ala3354Gly	missense_variant	Exon 26 of 29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.00255

AC:

388

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00888

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000637

AC:

160

AN:

251012

Hom.:

AF XY:

0.000442

AC XY:

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.00868

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000263

AC:

384

AN:

1461790

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

165

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00947

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.00254

AC:

387

AN:

152278

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

189

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00886

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000826

Hom.:

Bravo

AF:

0.00281

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000807

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:2

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

- -

Robarts Research Institute, Western University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Aug 10, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jan 23, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

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 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 03, 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. -

Familial hypercholesterolemia

Benign:1

Nov 06, 2023

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.92

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.86

M_CAP

Benign

0.013

MetaRNN

Benign

0.0069

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.0

REVEL

Benign

0.081

Sift

Benign

0.12

Sift4G

Pathogenic

0.0

Vest4

0.071

MVP

0.44

MPC

0.039

ClinPred

0.015

GERP RS

-0.33

gMVP

0.62

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