2-21036740-A-G

Variant names:

• chr2-21036740-A-G
• rs520354
• NM_000384.3:c.693+360T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000384.3(APOB):​c.693+360T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,032 control chromosomes in the GnomAD database, including 14,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.40 (14435 hom., cov: 31)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.208
• Publications: 36 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, type B

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-21036740-A-G is Benign according to our data. Variant chr2-21036740-A-G is described in ClinVar as Benign. ClinVar VariationId is 1619823.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.693+360T>C		intron_variant	Intron 6 of 28	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.693+360T>C		intron_variant	Intron 6 of 28	1	NM_000384.3	ENSP00000233242.1
APOB	ENST00000399256.4	c.693+360T>C		intron_variant	Intron 6 of 16	1		ENSP00000382200.4
APOB	ENST00000673739.2	n.539+360T>C		intron_variant	Intron 5 of 24			ENSP00000501110.2
APOB	ENST00000673882.2	n.539+360T>C		intron_variant	Intron 5 of 22			ENSP00000501253.2

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61395 AN: 151914 Hom.: 14444 Cov.: 31

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.428

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.404 AC: 61380 AN: 152032 Hom.: 14435 Cov.: 31 AF XY: 0.414 AC XY: 30763 AN XY: 74312

African (AFR) AF: 0.179 AC: 7431 AN: 41464

American (AMR) AF: 0.380 AC: 5814 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1307 AN: 3468

East Asian (EAS) AF: 0.855 AC: 4395 AN: 5142

South Asian (SAS) AF: 0.641 AC: 3081 AN: 4810

European-Finnish (FIN) AF: 0.571 AC: 6041 AN: 10584

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31966 AN: 67960

Other (OTH) AF: 0.430 AC: 905 AN: 2106

Alfa AF: 0.445 Hom.: 24412

Bravo AF: 0.375

Asia WGS AF: 0.703 AC: 2444 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.74
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs520354; hg19: chr2-21259612;