rs12713675

Variant names:

• chr2-21009501-G-T
• rs12713675
• NM_000384.3:c.7367C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000233242.5(APOB):​c.7367C>A​(p.Ala2456Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,026 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (56 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (54 hom.)
• Consequence: APOB ENST00000233242.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 0.799
• Publications: 9 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• familial hypobetalipoproteinemia 1

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• 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 (MetaRNN=0.0031191409).
• BP6: Variant 2-21009501-G-T is Benign according to our data. Variant chr2-21009501-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255987.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000233242.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.7367C>A	p.Ala2456Asp	missense	Exon 26 of 29	NP_000375.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.7367C>A	p.Ala2456Asp	missense	Exon 26 of 29	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2291 AN: 152116 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.0527

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00399 AC: 1001 AN: 251032 AF XY: 0.00313

Gnomad AFR exome AF: 0.0533

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00150 AC: 2197 AN: 1461792 Hom.: 54 Cov.: 60 AF XY: 0.00129 AC XY: 937 AN XY: 727194

African (AFR) AF: 0.0535 AC: 1791 AN: 33472

American (AMR) AF: 0.00262 AC: 117 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000728 AC: 81 AN: 1111950

Other (OTH) AF: 0.00306 AC: 185 AN: 60394

GnomAD4 genome AF: 0.0151 AC: 2293 AN: 152234 Hom.: 56 Cov.: 33 AF XY: 0.0152 AC XY: 1135 AN XY: 74430

African (AFR) AF: 0.0526 AC: 2183 AN: 41520

American (AMR) AF: 0.00510 AC: 78 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68018

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00674 Hom.: 19

Bravo AF: 0.0165

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00483 AC: 586

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	2	-	Hypercholesterolemia, familial, 1 (2)
-	-	1	Cardiovascular phenotype (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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.51	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.80
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.088
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.027	D
Vest4		0.17
MVP		0.46
MPC		0.12
ClinPred		0.031	T
GERP RS		2.2
gMVP		0.41
Mutation Taster		=91/9	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: rs12713675; hg19: chr2-21232373;