chr2-21043879-C-CCAGCAG

Variant names:

• chr2-21043879-C-CCAGCAG
• rs745520533
• NM_000384.3:c.61_66dupCTGCTG

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_000384.3(APOB):​c.61_66dupCTGCTG​(p.Leu21_Leu22dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,416,518 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L22L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00062 (17 hom.)
• Consequence: APOB NM_000384.3 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.29
• Publications: 2 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

ENSG00000299295 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000384.3.
• BP6: Variant 2-21043879-C-CCAGCAG is Benign according to our data. Variant chr2-21043879-C-CCAGCAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 426250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000621 (786/1265826) while in subpopulation AMR AF = 0.0243 (716/29458). AF 95% confidence interval is 0.0228. There are 17 homozygotes in GnomAdExome4. There are 318 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.61_66dupCTGCTG	p.Leu21_Leu22dup	conservative_inframe_insertion	Exon 1 of 29	NP_000375.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.61_66dupCTGCTG	p.Leu21_Leu22dup	conservative_inframe_insertion	Exon 1 of 29	ENSP00000233242.1
	APOB	ENST00000399256.4	TSL:1	c.61_66dupCTGCTG	p.Leu21_Leu22dup	conservative_inframe_insertion	Exon 1 of 17	ENSP00000382200.4
	APOB	ENST00000673739.2		n.61_66dupCTGCTG		non_coding_transcript_exon	Exon 1 of 25	ENSP00000501110.2

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 200 AN: 150590 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000850

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000890

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.00337 AC: 248 AN: 73646 AF XY: 0.00191

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.000621 AC: 786 AN: 1265826 Hom.: 17 Cov.: 31 AF XY: 0.000509 AC XY: 318 AN XY: 624992

African (AFR) AF: 0.000383 AC: 10 AN: 26132

American (AMR) AF: 0.0243 AC: 716 AN: 29458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30266

South Asian (SAS) AF: 0.0000139 AC: 1 AN: 72150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 0.0000281 AC: 28 AN: 997388

Other (OTH) AF: 0.000588 AC: 31 AN: 52728

GnomAD4 genome AF: 0.00132 AC: 199 AN: 150692 Hom.: 2 Cov.: 31 AF XY: 0.00134 AC XY: 99 AN XY: 73630

African (AFR) AF: 0.000848 AC: 35 AN: 41268

American (AMR) AF: 0.0101 AC: 153 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5116

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000890 AC: 6 AN: 67400

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.000141 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	APOB-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial hypercholesterolemia (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs745520533; hg19: chr2-21266751;