2-21036690-T-C

Variant names:

• chr2-21036690-T-C
• rs1469513
• NM_000384.3:c.693+410A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000384.3(APOB):​c.693+410A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,012 control chromosomes in the GnomAD database, including 9,600 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9600 hom., cov: 31)
• Consequence: APOB NM_000384.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• Publications: 36 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

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.693+410A>G		intron	N/A	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.693+410A>G		intron	N/A	ENSP00000233242.1	P04114
	APOB	ENST00000399256.4	TSL:1	c.693+410A>G		intron	N/A	ENSP00000382200.4	A8MUN2
	APOB	ENST00000673739.2		n.539+410A>G		intron	N/A	ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51437 AN: 151894 Hom.: 9600 Cov.: 31

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.333

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.338 AC: 51449 AN: 152012 Hom.: 9600 Cov.: 31 AF XY: 0.331 AC XY: 24586 AN XY: 74278

African (AFR) AF: 0.218 AC: 9044 AN: 41462

American (AMR) AF: 0.389 AC: 5936 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1066 AN: 3470

East Asian (EAS) AF: 0.106 AC: 548 AN: 5158

South Asian (SAS) AF: 0.207 AC: 991 AN: 4796

European-Finnish (FIN) AF: 0.318 AC: 3360 AN: 10578

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29209 AN: 67956

Other (OTH) AF: 0.332 AC: 701 AN: 2112

Alfa AF: 0.392 Hom.: 21919

Bravo AF: 0.340

Asia WGS AF: 0.163 AC: 572 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.8
DANN	Benign	0.85
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs1469513; hg19: chr2-21259562;