rs139704306

Positions:

• chr2-21005064-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000384.3(APOB):​c.11788+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,612,520 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.754

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-21005064-G-A is Benign according to our data. Variant chr2-21005064-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 490381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21005064-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.11788+16C>T		intron_variant		ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.11788+16C>T		intron_variant		1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00689

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00171 AC: 428 AN: 250762 Hom.: 4 AF XY: 0.00192 AC XY: 261 AN XY: 135632

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.00748

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.00143 AC: 2085 AN: 1460266 Hom.: 9 Cov.: 34 AF XY: 0.00152 AC XY: 1104 AN XY: 726444

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00295

Gnomad4 FIN exome AF: 0.00730

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74440

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00689

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00294 Hom.: 1

Bravo AF: 0.000559

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely 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:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Familial hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

GENinCode PLC

Jun 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs139704306; hg19: chr2-21227936;