2-21040767-T-G

Variant names:

• chr2-21040767-T-G
• rs531819
• NM_000384.3:c.383+171A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000384.3(APOB):​c.383+171A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 152,244 control chromosomes in the GnomAD database, including 53,175 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.83 (53175 hom., cov: 34)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• Publications: 17 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: ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial hypobetalipoproteinemia 1

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.383+171A>C		intron	N/A	NP_000375.3	P04114

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.383+171A>C		intron	N/A	ENSP00000233242.1	P04114
	APOB	ENST00000399256.4	TSL:1	c.383+171A>C		intron	N/A	ENSP00000382200.4	A8MUN2
	APOB	ENST00000673739.2		n.383+171A>C		intron	N/A	ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes AF: 0.834 AC: 126876 AN: 152126 Hom.: 53124 Cov.: 34

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.823

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

GnomAD4 genome AF: 0.834 AC: 126982 AN: 152244 Hom.: 53175 Cov.: 34 AF XY: 0.835 AC XY: 62163 AN XY: 74426

African (AFR) AF: 0.780 AC: 32395 AN: 41532

American (AMR) AF: 0.859 AC: 13144 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2283 AN: 3470

East Asian (EAS) AF: 0.996 AC: 5163 AN: 5182

South Asian (SAS) AF: 0.852 AC: 4105 AN: 4818

European-Finnish (FIN) AF: 0.857 AC: 9087 AN: 10600

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 57998 AN: 68024

Other (OTH) AF: 0.825 AC: 1745 AN: 2114

Alfa AF: 0.853 Hom.: 13302

Bravo AF: 0.832

Asia WGS AF: 0.932 AC: 3242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.5
DANN	Benign	0.78
PhyloP100		0.25
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: rs531819; hg19: chr2-21263639;