rs72653095

Positions:

• chr2-21008406-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000384.3(APOB):​c.8462C>T​(p.Pro2821Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,940 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2821P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (14 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:11
• Conservation: PhyloP100: 1.79

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077530444).
• BP6: Variant 2-21008406-G-A is Benign according to our data. Variant chr2-21008406-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218451.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=6, Uncertain_significance=3}. Variant chr2-21008406-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 14 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.8462C>T	p.Pro2821Leu	missense_variant	26/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.8462C>T	p.Pro2821Leu	missense_variant	26/29	1	NM_000384.3	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152028 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00406 AC: 1021 AN: 251208 Hom.: 6 AF XY: 0.00449 AC XY: 609 AN XY: 135774

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00983

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00853

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00424

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00399 AC: 5831 AN: 1461794 Hom.: 14 Cov.: 37 AF XY: 0.00414 AC XY: 3010 AN XY: 727204

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00838

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00834

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.00393

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.00278 AC XY: 207 AN XY: 74372

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.00114

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00389 Hom.: 3

Bravo AF: 0.00280

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00437 AC: 531

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00600

EpiControl AF: 0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2021	This variant is associated with the following publications: (PMID: 22995991, 24503134, 20657596, 18710658, 19602640, 27884173, 27153395, 30526649) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	APOB: BP4, BS2 -

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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: High frequency -

Familial hypobetalipoproteinemia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hypercholesterolemia, autosomal dominant, type B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2016

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

Nov 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.41	N
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.097
Sift	Benign	0.051	T
Sift4G	Uncertain	0.014	D
Vest4		0.27
MVP		0.67
MPC		0.28
ClinPred		0.019	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.67

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

Other links and lift over

dbSNP: rs72653095; hg19: chr2-21231278; COSMIC: COSV51941169;