chr2-21044060-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:3
• Conservation: PhyloP100: 1.49
• Publications: 11 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: 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 VariationId is 265871.
• 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 passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AD,AR,SD gene

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.-115C>G		5_prime_UTR	Exon 1 of 29	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.-115C>G		5_prime_UTR	Exon 1 of 29	ENSP00000233242.1	P04114
	APOB	ENST00000673739.2		n.-115C>G		non_coding_transcript_exon	Exon 1 of 25	ENSP00000501110.2	A0A669KB70
	APOB	ENST00000673882.2		n.-115C>G		non_coding_transcript_exon	Exon 1 of 23	ENSP00000501253.2	A0A669KB70

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

African (AFR) AF: 0.0392 AC: 241 AN: 6154

American (AMR) AF: 0.00646 AC: 35 AN: 5420

Ashkenazi Jewish (ASJ) AF: 0.000444 AC: 3 AN: 6758

East Asian (EAS) AF: 0.000232 AC: 4 AN: 17264

South Asian (SAS) AF: 0.00911 AC: 35 AN: 3840

European-Finnish (FIN) AF: 0.00465 AC: 87 AN: 18726

Middle Eastern (MID) AF: 0.0109 AC: 12 AN: 1096

European-Non Finnish (NFE) AF: 0.0105 AC: 2096 AN: 199642

Other (OTH) 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

African (AFR) AF: 0.0364 AC: 1512 AN: 41578

American (AMR) AF: 0.0141 AC: 216 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4828

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 853 AN: 67984

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.00586 Hom.: 3

Bravo AF: 0.0194

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Familial hypercholesterolemia (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B (1)
-	1	-	Hypercholesterolemia, familial, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.4
DANN	Benign	0.71
PhyloP100		1.5
PromoterAI		0.074	Neutral
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

Other links and lift over

dbSNP: rs1800480; hg19: chr2-21266932;