rs693

chr2-21009323-G-A

• Frequency:
  • Genomes: 𝑓 0.38 (12425 hom., cov: 32)
  • Exomes 𝑓: 0.39 (21368 hom.)
• Consequence: APOB NM_000384.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 0.126

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-21009323-G-A is Benign according to our data. Variant chr2-21009323-G-A is described in ClinVar as [Benign]. Clinvar id is 128425. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21009323-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.126 with no splicing effect.
• BA1: GnomAd highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.7545C>T	p.Thr2515=	synonymous_variant	26/29	ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.7545C>T	p.Thr2515=	synonymous_variant	26/29	1	NM_000384.3	P1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57860 AN: 151844 Hom.: 12425 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.0547

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.372

GnomAD3 exomes AF: 0.389 AC: 97584 AN: 251146 Hom.: 21368 AF XY: 0.391 AC XY: 53030 AN XY: 135726

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.381

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.0572

Gnomad SAS exome AF: 0.267

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.501

Gnomad OTH exome AF: 0.418

GnomAD4 exome AF: 0.467 AC: 683229 AN: 1461688 Hom.: 168652 AF XY: 0.462 AC XY: 335706 AN XY: 727126

Gnomad4 AFR exome AF: 0.209

Gnomad4 AMR exome AF: 0.382

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.0530

Gnomad4 SAS exome AF: 0.273

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.428

Alfa AF: 0.459 Hom.: 29043

Bravo AF: 0.375

Asia WGS AF: 0.165 AC: 578 AN: 3478

EpiCase AF: 0.486

EpiControl AF: 0.485

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not specified Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, PreventionGenetics	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypercholesterolemia, autosomal dominant, type B Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2022

- -

Hypercholesterolemia, familial, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 27, 2017

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2015

This alteration is classified as benign based on a combination of the following: 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, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 19, 2022

- -

Warfarin response Other:1

drug response, no assertion criteria provided

research

Pharmacogenomics Lab, Chungbuk National University

Aug 31, 2010

- likely responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

Cadd

Benign

5.4

Dann

Benign

0.86

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: rs693; hg19: chr2-21232195; COSMIC: COSV51935946;