2-21043879-CCAG-CCAGCAGCAGCAG

Position:

• chr2-21043879-CCAG-CCAGCAGCAGCAG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000384.3(APOB):​c.66_67insCTGCTGCTG​(p.Leu20_Leu22dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000158 in 1,265,872 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: APOB NM_000384.3 inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000384.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.66_67insCTGCTGCTG	p.Leu20_Leu22dup	inframe_insertion	1/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.66_67insCTGCTGCTG	p.Leu20_Leu22dup	inframe_insertion	1/29	1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000399256.4	c.66_67insCTGCTGCTG	p.Leu20_Leu22dup	inframe_insertion	1/17	1		ENSP00000382200
APOB	ENST00000673739.2	c.66_67insCTGCTGCTG	p.Leu20_Leu22dup	inframe_insertion, NMD_transcript_variant	1/25			ENSP00000501110
APOB	ENST00000673882.2	c.66_67insCTGCTGCTG	p.Leu20_Leu22dup	inframe_insertion, NMD_transcript_variant	1/23			ENSP00000501253

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1265872 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 625010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000100

Gnomad4 OTH exome AF: 0.0000190

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-21266751;