chr2-21028495-G-A

Variant names:

• chr2-21028495-G-A
• rs12714214
• NM_000384.3:c.1661C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000384.3(APOB):​c.1661C>T​(p.Pro554Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000497 in 1,613,704 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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. P554R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 6.82
• Publications: 16 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016731203).
• BP6: Variant 2-21028495-G-A is Benign according to our data. Variant chr2-21028495-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199684.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.1661C>T	p.Pro554Leu	missense_variant	Exon 13 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.1661C>T	p.Pro554Leu	missense_variant	Exon 13 of 29	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152138 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00898

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000681 AC: 171 AN: 251160 AF XY: 0.000501

Gnomad AFR exome AF: 0.00861

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000276 AC: 404 AN: 1461448 Hom.: 2 Cov.: 32 AF XY: 0.000256 AC XY: 186 AN XY: 727034

African (AFR) AF: 0.00774 AC: 259 AN: 33474

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53072

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000764 AC: 85 AN: 1111936

Other (OTH) AF: 0.000464 AC: 28 AN: 60392

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152256 Hom.: 4 Cov.: 33 AF XY: 0.00265 AC XY: 197 AN XY: 74446

African (AFR) AF: 0.00895 AC: 372 AN: 41562

American (AMR) AF: 0.00131 AC: 20 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000867 Hom.: 4

Bravo AF: 0.00283

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000898 AC: 109

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Apr 04, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APOB: BP4 -

Sep 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Uncertain: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

- -

Familial hypobetalipoproteinemia 1 Uncertain:1

Aug 30, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Jan 27, 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

Aug 30, 2018

Illumina Laboratory Services, Illumina

Significance: 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Jul 30, 2019

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

Jun 19, 2024

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	0.11
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D
MetaRNN	Benign	0.017	T;T
MetaSVM	Uncertain	0.054	D
PhyloP100		6.8
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.66
MVP		0.91
MPC		0.28
ClinPred		0.11	T
GERP RS		5.7
gMVP		0.40
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs12714214; hg19: chr2-21251367; COSMIC: COSV51942816; COSMIC: COSV51942816;