2-21003346-GAAA-GAAAAAA

Variant names:

• chr2-21003346-G-GAAA
• rs751121092
• NM_000384.3:c.12088-15_12088-13dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000384.3(APOB):​c.12088-15_12088-13dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000178 in 1,122,808 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: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.342
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.12088-15_12088-13dupTTT		intron	N/A	NP_000375.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.12088-13_12088-12insTTT		intron	N/A	ENSP00000233242.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000178 AC: 2 AN: 1122808 Hom.: 0 Cov.: 29 AF XY: 0.00000358 AC XY: 2 AN XY: 558100

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24916

American (AMR) AF: 0.00 AC: 0 AN: 32642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19084

East Asian (EAS) AF: 0.00 AC: 0 AN: 30322

South Asian (SAS) AF: 0.00 AC: 0 AN: 64198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4638

European-Non Finnish (NFE) AF: 0.00000231 AC: 2 AN: 864412

Other (OTH) AF: 0.00 AC: 0 AN: 45626

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34

Splicing

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

Other links and lift over

dbSNP: rs751121092; hg19: chr2-21226218;