2-21021128-G-T

Position:

• chr2-21021128-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000384.3(APOB):​c.2817-1223C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 152,072 control chromosomes in the GnomAD database, including 10,025 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 0.35 (10025 hom., cov: 32)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.964

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.2817-1223C>A		intron_variant		ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.2817-1223C>A		intron_variant		1	NM_000384.3	ENSP00000233242.1
APOB	ENST00000673739.2	n.*2123-1223C>A		intron_variant				ENSP00000501110.2
APOB	ENST00000673882.2	n.*2123-1223C>A		intron_variant				ENSP00000501253.2

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52834 AN: 151954 Hom.: 10026 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.340

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

GnomAD4 genome AF: 0.348 AC: 52846 AN: 152072 Hom.: 10025 Cov.: 32 AF XY: 0.339 AC XY: 25189 AN XY: 74354

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.436

Gnomad4 OTH AF: 0.338

Alfa AF: 0.405 Hom.: 14393

Bravo AF: 0.349

Asia WGS AF: 0.148 AC: 520 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	11
DANN	Benign	0.72

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

Other links and lift over

dbSNP: rs10199768; hg19: chr2-21244000;