2-21018633-A-G

Variant names:

• chr2-21018633-A-G
• rs12713956
• NM_000384.3:c.3121+359T>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.3121+359T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 151,990 control chromosomes in the GnomAD database, including 1,546 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 0.13 (1546 hom., cov: 32)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.3121+359T>C		intron_variant	Intron 20 of 28	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.3121+359T>C		intron_variant	Intron 20 of 28	1	NM_000384.3	ENSP00000233242.1
APOB	ENST00000673739.2	n.*2427+359T>C		intron_variant	Intron 19 of 24			ENSP00000501110.2
APOB	ENST00000673882.2	n.*2427+359T>C		intron_variant	Intron 19 of 22			ENSP00000501253.2

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20435 AN: 151872 Hom.: 1541 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.0396

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0948

Gnomad OTH AF: 0.139

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

GnomAD4 genome AF: 0.135 AC: 20476 AN: 151990 Hom.: 1546 Cov.: 32 AF XY: 0.137 AC XY: 10206 AN XY: 74286

African (AFR) AF: 0.188 AC: 7785 AN: 41442

American (AMR) AF: 0.177 AC: 2705 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 994 AN: 3468

East Asian (EAS) AF: 0.0399 AC: 206 AN: 5164

South Asian (SAS) AF: 0.113 AC: 544 AN: 4800

European-Finnish (FIN) AF: 0.129 AC: 1366 AN: 10576

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.0948 AC: 6440 AN: 67958

Other (OTH) AF: 0.139 AC: 293 AN: 2114

Alfa AF: 0.114 Hom.: 3057

Bravo AF: 0.143

Asia WGS AF: 0.0870 AC: 303 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.74
PhyloP100		-0.24
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: rs12713956; hg19: chr2-21241505;