rs72653066

Positions:

• chr2-21023510-C-G

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.2604+15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,002 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (20 hom., cov: 32)
  • Exomes 𝑓: 0.011 (159 hom.)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.15

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-21023510-C-G is Benign according to our data. Variant chr2-21023510-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 255980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-21023510-C-G is described in Lovd as [Benign]. Variant chr2-21023510-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 20 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOB	NM_000384.3	c.2604+15G>C		intron_variant		ENST00000233242.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOB	ENST00000233242.5	c.2604+15G>C		intron_variant		1	NM_000384.3	P1
	ENST00000624225.1	n.15C>G		non_coding_transcript_exon_variant	1/1
APOB	ENST00000673739.2	c.*1910+15G>C		intron_variant, NMD_transcript_variant
APOB	ENST00000673882.2	c.*1910+15G>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00829 AC: 1261 AN: 152148 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00899 AC: 2260 AN: 251316 Hom.: 40 AF XY: 0.00920 AC XY: 1250 AN XY: 135814

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0808

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0106 AC: 15547 AN: 1461736 Hom.: 159 Cov.: 31 AF XY: 0.0105 AC XY: 7655 AN XY: 727184

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.0802

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00248

Gnomad4 FIN exome AF: 0.00331

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.00827 AC: 1260 AN: 152266 Hom.: 20 Cov.: 32 AF XY: 0.00735 AC XY: 547 AN XY: 74456

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0188 Hom.: 8

Bravo AF: 0.00822

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hypercholesterolemia, autosomal dominant, type B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 26, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hypercholesterolemia, familial, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Robarts Research Institute, Western University

Jan 02, 2018

- -

Familial hypobetalipoproteinemia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 26, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

GENinCode PLC

Jun 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.40
DANN	Benign	0.39

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: rs72653066; hg19: chr2-21246382;