chr2-21006574-G-C

Variant names:

• chr2-21006574-G-C
• rs1042023
• NM_000384.3:c.10294C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000384.3(APOB):​c.10294C>G​(p.Gln3432Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00922 in 1,614,016 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q3432R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0067 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0095 (91 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.30
• Publications: 21 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006468892).
• BP6: Variant 2-21006574-G-C is Benign according to our data. Variant chr2-21006574-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 180279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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.10294C>G	p.Gln3432Glu	missense	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.10294C>G	p.Gln3432Glu	missense	Exon 26 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.00665 AC: 1012 AN: 152136 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00723 AC: 1816 AN: 251196 AF XY: 0.00725

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00994

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.00948 AC: 13861 AN: 1461762 Hom.: 91 Cov.: 36 AF XY: 0.00916 AC XY: 6660 AN XY: 727186

African (AFR) AF: 0.00114 AC: 38 AN: 33464

American (AMR) AF: 0.00483 AC: 216 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00172 AC: 148 AN: 86254

European-Finnish (FIN) AF: 0.00992 AC: 530 AN: 53410

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.0111 AC: 12356 AN: 1111930

Other (OTH) AF: 0.00871 AC: 526 AN: 60392

GnomAD4 genome AF: 0.00665 AC: 1013 AN: 152254 Hom.: 2 Cov.: 33 AF XY: 0.00608 AC XY: 453 AN XY: 74452

African (AFR) AF: 0.00195 AC: 81 AN: 41560

American (AMR) AF: 0.00484 AC: 74 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.00933 AC: 99 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 724 AN: 68006

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00945 Hom.: 6

Bravo AF: 0.00624

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.00759 AC: 921

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00948

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	Hypercholesterolemia, familial, 1 (5)
-	-	4	not specified (4)
-	-	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	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.32	T
PhyloP100		2.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.31
Sift	Benign	0.042	D
Sift4G	Uncertain	0.031	D
Vest4		0.16
MVP		0.84
MPC		0.049
ClinPred		0.021	T
GERP RS		5.7
gMVP		0.31
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: rs1042023; hg19: chr2-21229446; COSMIC: COSV99028656;