rs745520533

Positions:

• chr2-21043879-CCAG-C
• chr2-21043879-CCAG-CCAGCAG
• chr2-21043879-CCAG-CCAGCAGCAG
• chr2-21043879-CCAG-CCAGCAGCAGCAG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2 PM4_Supporting BP6_Very_Strong

The NM_000384.3(APOB):​c.64_66del​(p.Leu22del) variant causes a 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 (★★).

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

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 1168150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21043879-CCAG-C is described in Lovd as [Benign]. Variant chr2-21043879-CCAG-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.64_66del	p.Leu22del	inframe_deletion	1/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.64_66del	p.Leu22del	inframe_deletion	1/29	1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000399256.4	c.64_66del	p.Leu22del	inframe_deletion	1/17	1		ENSP00000382200
APOB	ENST00000673739.2	c.64_66del	p.Leu22del	inframe_deletion, NMD_transcript_variant	1/25			ENSP00000501110
APOB	ENST00000673882.2	c.64_66del	p.Leu22del	inframe_deletion, NMD_transcript_variant	1/23			ENSP00000501253

Frequencies

GnomAD3 genomes AF: 0.00 AC: 6 AN: 150460 Hom.: 0 Cov.: 31 FAILED QC

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

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

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00757

Gnomad4 ASJ exome AF: 0.00362

Gnomad4 EAS exome AF: 0.00305

Gnomad4 SAS exome AF: 0.00641

Gnomad4 FIN exome AF: 0.00267

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.00220

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

Gnomad4 AFR AF: 0.0000486

Gnomad4 AMR AF: 0.0000664

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000978

Gnomad4 NFE AF: 0.0000297

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0113 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

GENinCode PLC

Feb 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs745520533; hg19: chr2-21266751;