2-21043856-G-T

Variant names:

• chr2-21043856-G-T
• rs932043593
• NM_000384.3:c.82+8C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000384.3(APOB):​c.82+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,368,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: APOB NM_000384.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002489
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.57
• 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: 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

ENSG00000299295 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-21043856-G-T is Benign according to our data. Variant chr2-21043856-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 619780.

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.82+8C>A		splice_region 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.82+8C>A		splice_region intron	N/A	ENSP00000233242.1	P04114
	APOB	ENST00000399256.4	TSL:1	c.82+8C>A		splice_region intron	N/A	ENSP00000382200.4	A8MUN2
	APOB	ENST00000673739.2		n.82+8C>A		splice_region intron	N/A	ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000263 AC: 36 AN: 1368674 Hom.: 0 Cov.: 31 AF XY: 0.0000237 AC XY: 16 AN XY: 675452

African (AFR) AF: 0.00 AC: 0 AN: 30088

American (AMR) AF: 0.00 AC: 0 AN: 35076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24384

East Asian (EAS) AF: 0.00 AC: 0 AN: 34444

South Asian (SAS) AF: 0.00 AC: 0 AN: 78100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4498

European-Non Finnish (NFE) AF: 0.0000336 AC: 36 AN: 1071886

Other (OTH) AF: 0.00 AC: 0 AN: 56910

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.69
DANN	Benign	0.82
PhyloP100		-3.6
PromoterAI		-0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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: rs932043593; hg19: chr2-21266728;