rs61746672

Positions:

chr2-21037187-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000384.3(APOB):c.606A>T(p.Glu202Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000742 in 1,614,204 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 5 hom. )

Consequence

APOB
NM_000384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.0360

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060367286).

BP6

Variant 2-21037187-T-A is Benign according to our data. Variant chr2-21037187-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 235263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21037187-T-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3 link	c.606A>T	p.Glu202Asp	missense_variant	6/29	ENST00000233242.5	NP_000375.3	P04114Q7Z7Q0Q59HB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
APOB	ENST00000233242.5 link	c.606A>T	p.Glu202Asp	missense_variant	6/29	1	NM_000384.3	ENSP00000233242.1	P04114
APOB	ENST00000399256.4 link	c.606A>T	p.Glu202Asp	missense_variant	6/17	1		ENSP00000382200.4	A8MUN2
APOB	ENST00000673739.2 link	n.452A>T		non_coding_transcript_exon_variant	5/25			ENSP00000501110.2	A0A669KB70
APOB	ENST00000673882.2 link	n.452A>T		non_coding_transcript_exon_variant	5/23			ENSP00000501253.2	A0A669KB70

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

539

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00112

AC:

282

AN:

251446

Hom.:

AF XY:

0.000839

AC XY:

114

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.00136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000451

AC:

659

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000378

AC XY:

275

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0141

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000692

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.00354

AC:

539

AN:

152314

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0123

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000608

Hom.:

Bravo

AF:

0.00424

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00119

AC:

145

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	APOB: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2020	- -

Familial hypercholesterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2018	- -

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, familial, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Robarts Research Institute, Western University

Jan 02, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2017

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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

6.9

DANN

Benign

0.95

DEOGEN2

Benign

0.013

.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.68

.;T

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.56

N;N

REVEL

Benign

0.047

Sift

Benign

0.71

T;T

Sift4G

Benign

0.17

T;T

Vest4

0.083

MutPred

0.46

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

0.47

MPC

0.063

ClinPred

0.0089

GERP RS

0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.46

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