rs1041968

Positions:

chr2-21009932-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000384.3(APOB):c.6936C>T(p.Asp2312Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,613,400 control chromosomes in the GnomAD database, including 181,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 12426 hom., cov: 33)

Exomes 𝑓: 0.47 ( 168579 hom. )

Consequence

APOB
NM_000384.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.386

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 2-21009932-G-A is Benign according to our data. Variant chr2-21009932-G-A is described in ClinVar as [Benign]. Clinvar id is 1169879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21009932-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.386 with no splicing effect.

BA1

GnomAd4 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	Protein	UniProt
APOB	NM_000384.3 linkuse as main transcript	c.6936C>T	p.Asp2312Asp	synonymous_variant	26/29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5 linkuse as main transcript	c.6936C>T	p.Asp2312Asp	synonymous_variant	26/29	1	NM_000384.3	ENSP00000233242.1		P04114

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57852

AN:

152002

Hom.:

12426

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.533

Gnomad AMR

AF:

0.411

Gnomad ASJ

AF:

0.355

Gnomad EAS

AF:

0.0542

Gnomad SAS

AF:

0.239

Gnomad FIN

AF:

0.386

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.500

Gnomad OTH

AF:

0.372

GnomAD3 exomes

AF:

0.388

AC:

97366

AN:

250982

Hom.:

21331

AF XY:

0.390

AC XY:

52891

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.380

Gnomad ASJ exome

AF:

0.346

Gnomad EAS exome

AF:

0.0569

Gnomad SAS exome

AF:

0.261

Gnomad FIN exome

AF:

0.404

Gnomad NFE exome

AF:

0.501

Gnomad OTH exome

AF:

0.419

GnomAD4 exome

AF:

0.467

AC:

682753

AN:

1461280

Hom.:

168579

Cov.:

AF XY:

0.461

AC XY:

335379

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.209

Gnomad4 AMR exome

AF:

0.381

Gnomad4 ASJ exome

AF:

0.353

Gnomad4 EAS exome

AF:

0.0527

Gnomad4 SAS exome

AF:

0.267

Gnomad4 FIN exome

AF:

0.411

Gnomad4 NFE exome

AF:

0.517

Gnomad4 OTH exome

AF:

0.428

GnomAD4 genome

AF:

0.380

AC:

57857

AN:

152120

Hom.:

12426

Cov.:

AF XY:

0.371

AC XY:

27591

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.229

Gnomad4 AMR

AF:

0.411

Gnomad4 ASJ

AF:

0.355

Gnomad4 EAS

AF:

0.0541

Gnomad4 SAS

AF:

0.240

Gnomad4 FIN

AF:

0.386

Gnomad4 NFE

AF:

0.500

Gnomad4 OTH

AF:

0.370

Alfa

AF:

0.454

Hom.:

11218

Bravo

AF:

0.375

Asia WGS

AF:

0.164

AC:

575

AN:

3478

EpiCase

AF:

0.486

EpiControl

AF:

0.485

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Familial hypercholesterolemia

Benign:2

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 21, 2022	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2021

- -

Hypercholesterolemia, autosomal dominant, type B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Familial hypobetalipoproteinemia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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: 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

-0.91

CADD

Benign

0.57

DANN

Benign

0.19

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