rs6413458

Variant names:

• chr2-21008720-G-A
• rs6413458
• NM_000384.3:c.8148C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-21008720-G-A
• chr2-21008720-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000384.3(APOB):​c.8148C>T​(p.Ile2716Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,614,008 control chromosomes in the GnomAD database, including 404 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 0.022 (61 hom., cov: 32)
  • Exomes 𝑓: 0.019 (343 hom.)
• Consequence: APOB NM_000384.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: -0.186
• Publications: 20 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-21008720-G-A is Benign according to our data. Variant chr2-21008720-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237751.
• BP7: Synonymous conserved (PhyloP=-0.186 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.022 (3344/152224) while in subpopulation AFR AF = 0.0323 (1342/41550). AF 95% confidence interval is 0.0309. There are 61 homozygotes in GnomAd4. There are 1625 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 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.8148C>T	p.Ile2716Ile	synonymous	Exon 26 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.8148C>T	p.Ile2716Ile	synonymous	Exon 26 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3340 AN: 152106 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0323

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0185 AC: 4657 AN: 251164 AF XY: 0.0177

Gnomad AFR exome AF: 0.0319

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0584

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0188 AC: 27552 AN: 1461784 Hom.: 343 Cov.: 46 AF XY: 0.0186 AC XY: 13518 AN XY: 727194

African (AFR) AF: 0.0325 AC: 1089 AN: 33470

American (AMR) AF: 0.0111 AC: 495 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 1538 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0114 AC: 985 AN: 86252

European-Finnish (FIN) AF: 0.0240 AC: 1284 AN: 53418

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5766

European-Non Finnish (NFE) AF: 0.0187 AC: 20787 AN: 1111930

Other (OTH) AF: 0.0213 AC: 1284 AN: 60396

GnomAD4 genome AF: 0.0220 AC: 3344 AN: 152224 Hom.: 61 Cov.: 32 AF XY: 0.0218 AC XY: 1625 AN XY: 74426

African (AFR) AF: 0.0323 AC: 1342 AN: 41550

American (AMR) AF: 0.0124 AC: 190 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4830

European-Finnish (FIN) AF: 0.0226 AC: 239 AN: 10594

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0183 AC: 1245 AN: 68008

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0231 Hom.: 53

Bravo AF: 0.0218

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0161

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	Hypercholesterolemia, familial, 1 (3)
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.4
DANN	Benign	0.63
PhyloP100		-0.19
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: rs6413458; hg19: chr2-21231592; COSMIC: COSV51928442;