chr2-21032396-C-T

Position:

chr2-21032396-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000233242.5(APOB):c.1310G>A(p.Arg437His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R437L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

APOB
ENST00000233242.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.00200

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008685529).

BP6

Variant 2-21032396-C-T is Benign according to our data. Variant chr2-21032396-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252480.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}. Variant chr2-21032396-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	10/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
APOB	ENST00000233242.5 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	10/29	1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000399256.4 linkuse as main transcript	c.1310G>A	p.Arg437His	missense_variant	10/17	1		ENSP00000382200
APOB	ENST00000673739.2 linkuse as main transcript	c.*616G>A		3_prime_UTR_variant, NMD_transcript_variant	9/25			ENSP00000501110
APOB	ENST00000673882.2 linkuse as main transcript	c.*616G>A		3_prime_UTR_variant, NMD_transcript_variant	9/23			ENSP00000501253

Frequencies

GnomAD3 genomes

AF:

0.000953

AC:

145

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00340

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000271

AC:

AN:

251058

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1461646

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00457

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000959

AC:

146

AN:

152320

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00342

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000524

Hom.:

Bravo

AF:

0.00131

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 30, 2015	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

APOB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Dec 23, 2020

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.76

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.94

N;N

PrimateAI

Benign

0.18

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.030

Sift

Benign

0.076

T;T

Sift4G

Uncertain

0.013

D;T

Vest4

0.078

MVP

0.47

MPC

0.17

ClinPred

0.039

GERP RS

-0.66

gMVP

0.12

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