2-21003346-GAAA-GAAAA

Variant names:

• chr2-21003346-G-GA
• rs751121092
• NM_000384.3:c.12088-13dupT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000384.3(APOB):​c.12088-13dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 1,091,966 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.033 (3 hom.)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.342
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 2-21003346-G-GA is Benign according to our data. Variant chr2-21003346-G-GA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334083.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,SD gene

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.12088-13dupT		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.12088-13_12088-12insT		intron	N/A	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 142 AN: 137534 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000724

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00249

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.000127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000318

Gnomad OTH AF: 0.000526

GnomAD2 exomes AF: 0.0126 AC: 1788 AN: 141744 AF XY: 0.0137

Gnomad AFR exome AF: 0.00547

Gnomad AMR exome AF: 0.0143

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00669

Gnomad FIN exome AF: 0.0236

Gnomad NFE exome AF: 0.00695

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0327 AC: 31172 AN: 954370 Hom.: 3 Cov.: 29 AF XY: 0.0317 AC XY: 14969 AN XY: 471794

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

African (AFR) AF: 0.0293 AC: 609 AN: 20820

American (AMR) AF: 0.0132 AC: 356 AN: 26966

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 318 AN: 14948

East Asian (EAS) AF: 0.0151 AC: 370 AN: 24470

South Asian (SAS) AF: 0.0438 AC: 2272 AN: 51848

European-Finnish (FIN) AF: 0.0197 AC: 614 AN: 31240

Middle Eastern (MID) AF: 0.0178 AC: 73 AN: 4104

European-Non Finnish (NFE) AF: 0.0342 AC: 25359 AN: 742168

Other (OTH) AF: 0.0318 AC: 1201 AN: 37806

⚠️ 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 AF: 0.00104 AC: 143 AN: 137596 Hom.: 1 Cov.: 32 AF XY: 0.00139 AC XY: 92 AN XY: 66416

African (AFR) AF: 0.000720 AC: 27 AN: 37502

American (AMR) AF: 0.000723 AC: 10 AN: 13840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3250

East Asian (EAS) AF: 0.00249 AC: 12 AN: 4812

South Asian (SAS) AF: 0.0164 AC: 72 AN: 4392

European-Finnish (FIN) AF: 0.000127 AC: 1 AN: 7858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.000318 AC: 20 AN: 62918

Other (OTH) AF: 0.000521 AC: 1 AN: 1920

Alfa AF: 0.0395 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Familial hypobetalipoproteinemia (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)
-	1	-	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751121092; hg19: chr2-21226218; COSMIC: COSV51938376; COSMIC: COSV51938376;