2-21043879-CCAG-C

Variant names:

• chr2-21043879-CCAG-C
• rs745520533
• NM_000384.3:c.64_66delCTG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PM4_Supporting BP6_Very_Strong

The NM_000384.3(APOB):​c.64_66delCTG​(p.Leu22del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,176,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L22L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APOB NM_000384.3 conservative_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.33
• 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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000384.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-21043879-CCAG-C is Benign according to our data. Variant chr2-21043879-CCAG-C is described in ClinVar as Benign. ClinVar VariationId is 1168150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.64_66delCTG	p.Leu22del	conservative_inframe_deletion	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.64_66delCTG	p.Leu22del	conservative_inframe_deletion	Exon 1 of 29	ENSP00000233242.1
	APOB	ENST00000399256.4	TSL:1	c.64_66delCTG	p.Leu22del	conservative_inframe_deletion	Exon 1 of 17	ENSP00000382200.4
	APOB	ENST00000673739.2		n.64_66delCTG		non_coding_transcript_exon	Exon 1 of 25	ENSP00000501110.2

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 6 AN: 150460 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000664

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000978

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000297

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00968 AC: 713 AN: 73646 AF XY: 0.00901

Gnomad AFR exome AF: 0.00370

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00867

Gnomad EAS exome AF: 0.0203

Gnomad FIN exome AF: 0.00850

Gnomad NFE exome AF: 0.00890

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00200 AC: 2349 AN: 1176340 Hom.: 0 AF XY: 0.00231 AC XY: 1342 AN XY: 580032

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

African (AFR) AF: 0.00129 AC: 32 AN: 24888

American (AMR) AF: 0.00757 AC: 207 AN: 27340

Ashkenazi Jewish (ASJ) AF: 0.00362 AC: 76 AN: 21004

East Asian (EAS) AF: 0.00305 AC: 88 AN: 28888

South Asian (SAS) AF: 0.00641 AC: 424 AN: 66116

European-Finnish (FIN) AF: 0.00267 AC: 77 AN: 28880

Middle Eastern (MID) AF: 0.00239 AC: 9 AN: 3758

European-Non Finnish (NFE) AF: 0.00143 AC: 1328 AN: 926446

Other (OTH) AF: 0.00220 AC: 108 AN: 49020

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000399 AC: 6 AN: 150460 Hom.: 0 Cov.: 31 AF XY: 0.0000408 AC XY: 3 AN XY: 73440

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

African (AFR) AF: 0.0000486 AC: 2 AN: 41134

American (AMR) AF: 0.0000664 AC: 1 AN: 15050

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.0000978 AC: 1 AN: 10226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000297 AC: 2 AN: 67366

Other (OTH) AF: 0.00 AC: 0 AN: 2066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000209190), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0113 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs745520533; hg19: chr2-21266751; COSMIC: COSV51950295;