2-21015452-C-T

Variant names:

• chr2-21015452-C-T
• rs142448733
• NM_000384.3:c.3426G>A

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.3426G>A​(p.Ser1142Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,614,016 control chromosomes in the GnomAD database, including 14 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 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (13 hom.)
• Consequence: APOB NM_000384.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: -0.250
• Publications: 5 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-21015452-C-T is Benign according to our data. Variant chr2-21015452-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334155.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00136 (1993/1461886) while in subpopulation MID AF = 0.0224 (129/5768). AF 95% confidence interval is 0.0192. There are 13 homozygotes in GnomAdExome4. There are 1054 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.3426G>A	p.Ser1142Ser	synonymous	Exon 22 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.3426G>A	p.Ser1142Ser	synonymous	Exon 22 of 29	ENSP00000233242.1	P04114
	APOB	ENST00000673739.2		n.*2732G>A		non_coding_transcript_exon	Exon 21 of 25	ENSP00000501110.2	A0A669KB70
	APOB	ENST00000673882.2		n.*2521G>A		non_coding_transcript_exon	Exon 20 of 23	ENSP00000501253.2	A0A669KB70

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152012 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00215 AC: 541 AN: 251448 AF XY: 0.00226

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00136 AC: 1993 AN: 1461886 Hom.: 13 Cov.: 33 AF XY: 0.00145 AC XY: 1054 AN XY: 727246

African (AFR) AF: 0.00167 AC: 56 AN: 33480

American (AMR) AF: 0.00217 AC: 97 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 625 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00159 AC: 137 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53418

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5768

European-Non Finnish (NFE) AF: 0.000658 AC: 732 AN: 1112006

Other (OTH) AF: 0.00349 AC: 211 AN: 60396

GnomAD4 genome AF: 0.00187 AC: 284 AN: 152130 Hom.: 1 Cov.: 32 AF XY: 0.00182 AC XY: 135 AN XY: 74370

African (AFR) AF: 0.000651 AC: 27 AN: 41494

American (AMR) AF: 0.00366 AC: 56 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 68008

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00228 Hom.: 0

Bravo AF: 0.00178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Familial hypercholesterolemia (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Familial hypobetalipoproteinemia 1 (1)
-	1	-	Hypercholesterolemia, autosomal dominant, type B (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)
-	-	1	Hypercholesterolemia, familial, 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.3
DANN	Benign	0.73
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	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: rs142448733; hg19: chr2-21238324; COSMIC: COSV51948770;