2-21022941-G-A

Position:

• chr2-21022941-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The ENST00000233242.5(APOB):​c.2706C>T​(p.Asn902=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,614,096 control chromosomes in the GnomAD database, including 1,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.035 (143 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1801 hom.)
• Consequence: APOB ENST00000233242.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.74

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-21022941-G-A is Benign according to our data. Variant chr2-21022941-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255981.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=1, Uncertain_significance=1}. Variant chr2-21022941-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.2706C>T	p.Asn902=	synonymous_variant	18/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.2706C>T	p.Asn902=	synonymous_variant	18/29	1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000673739.2	c.*2012C>T		3_prime_UTR_variant, NMD_transcript_variant	17/25			ENSP00000501110
APOB	ENST00000673882.2	c.*2012C>T		3_prime_UTR_variant, NMD_transcript_variant	17/23			ENSP00000501253

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5383 AN: 152128 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.00804

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0681

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0354 AC: 8898 AN: 251400 Hom.: 185 AF XY: 0.0363 AC XY: 4928 AN XY: 135862

Gnomad AFR exome AF: 0.00849

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0246

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0465 AC: 68032 AN: 1461850 Hom.: 1801 Cov.: 32 AF XY: 0.0461 AC XY: 33528 AN XY: 727228

Gnomad4 AFR exome AF: 0.00753

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0272

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0250

Gnomad4 FIN exome AF: 0.0593

Gnomad4 NFE exome AF: 0.0527

Gnomad4 OTH exome AF: 0.0364

GnomAD4 genome AF: 0.0354 AC: 5385 AN: 152246 Hom.: 143 Cov.: 32 AF XY: 0.0358 AC XY: 2668 AN XY: 74454

Gnomad4 AFR AF: 0.00802

Gnomad4 AMR AF: 0.0263

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.0681

Gnomad4 NFE AF: 0.0525

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0446 Hom.: 102

Bravo AF: 0.0308

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0489

EpiControl AF: 0.0509

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2016	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. -

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	Aug 04, 2017	- -

Hypercholesterolemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Mar 01, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hypercholesterolemia, autosomal dominant, type B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial hypobetalipoproteinemia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

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
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.5
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1801700; hg19: chr2-21245813;