2-21044060-G-C

Variant names:

• chr2-21044060-G-C
• rs1800480
• NM_000384.3:c.-115C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000384.3(APOB):​c.-115C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 425,854 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (27 hom.)
• Consequence: APOB NM_000384.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.49

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-21044060-G-C is Benign according to our data. Variant chr2-21044060-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265871.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0177 (2699/152250) while in subpopulation AFR AF = 0.0364 (1512/41578). AF 95% confidence interval is 0.0348. There are 35 homozygotes in GnomAd4. There are 1223 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOB	NM_000384.3	c.-115C>G		5_prime_UTR_variant	Exon 1 of 29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.-115C>G		5_prime_UTR_variant	Exon 1 of 29	1	NM_000384.3	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2699 AN: 152134 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.00988 AC: 2703 AN: 273604 Hom.: 27 Cov.: 5 AF XY: 0.00932 AC XY: 1290 AN XY: 138474

Gnomad4 AFR exome AF: 0.0392 AC: 241 AN: 6154

Gnomad4 AMR exome AF: 0.00646 AC: 35 AN: 5420

Gnomad4 ASJ exome AF: 0.000444 AC: 3 AN: 6758

Gnomad4 EAS exome AF: 0.000232 AC: 4 AN: 17264

Gnomad4 SAS exome AF: 0.00911 AC: 35 AN: 3840

Gnomad4 FIN exome AF: 0.00465 AC: 87 AN: 18726

Gnomad4 NFE exome AF: 0.0105 AC: 2096 AN: 199642

Gnomad4 Remaining exome AF: 0.0129 AC: 190 AN: 14704

GnomAD4 genome AF: 0.0177 AC: 2699 AN: 152250 Hom.: 35 Cov.: 32 AF XY: 0.0164 AC XY: 1223 AN XY: 74452

Gnomad4 AFR AF: 0.0364 AC: 0.0363654 AN: 0.0363654

Gnomad4 AMR AF: 0.0141 AC: 0.0141195 AN: 0.0141195

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000387 AC: 0.000386847 AN: 0.000386847

Gnomad4 SAS AF: 0.0106 AC: 0.0105634 AN: 0.0105634

Gnomad4 FIN AF: 0.00274 AC: 0.00273585 AN: 0.00273585

Gnomad4 NFE AF: 0.0125 AC: 0.0125471 AN: 0.0125471

Gnomad4 OTH AF: 0.0165 AC: 0.0165406 AN: 0.0165406

Alfa AF: 0.00586 Hom.: 3

Bravo AF: 0.0194

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hypercholesterolemia, autosomal dominant, type B Benign:1

Apr 24, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Familial hypercholesterolemia Benign:1

Aug 03, 2023

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.4
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs1800480; hg19: chr2-21266932;