2-21002881-C-T

Variant names:

• chr2-21002881-C-T
• rs1042031
• NM_000384.3:c.12541G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000384.3(APOB):​c.12541G>A​(p.Glu4181Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,612,886 control chromosomes in the GnomAD database, including 23,921 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. E4181D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2057 hom., cov: 31)
  • Exomes 𝑓: 0.17 (21864 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.151
• Publications: 125 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026869774).
• BP6: Variant 2-21002881-C-T is Benign according to our data. Variant chr2-21002881-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 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.12541G>A	p.Glu4181Lys	missense	Exon 29 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.12541G>A	p.Glu4181Lys	missense	Exon 29 of 29	ENSP00000233242.1	P04114

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25020 AN: 151820 Hom.: 2054 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.0930

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.153 AC: 38224 AN: 249978 AF XY: 0.154

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.0484

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.169 AC: 246533 AN: 1460948 Hom.: 21864 Cov.: 37 AF XY: 0.167 AC XY: 121538 AN XY: 726684

African (AFR) AF: 0.150 AC: 5031 AN: 33438

American (AMR) AF: 0.124 AC: 5551 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3777 AN: 26096

East Asian (EAS) AF: 0.0440 AC: 1745 AN: 39688

South Asian (SAS) AF: 0.102 AC: 8812 AN: 86088

European-Finnish (FIN) AF: 0.204 AC: 10874 AN: 53280

Middle Eastern (MID) AF: 0.124 AC: 717 AN: 5760

European-Non Finnish (NFE) AF: 0.180 AC: 200535 AN: 1111636

Other (OTH) AF: 0.157 AC: 9491 AN: 60360

GnomAD4 genome AF: 0.165 AC: 25037 AN: 151938 Hom.: 2057 Cov.: 31 AF XY: 0.164 AC XY: 12185 AN XY: 74268

African (AFR) AF: 0.152 AC: 6316 AN: 41418

American (AMR) AF: 0.145 AC: 2212 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3472

East Asian (EAS) AF: 0.0461 AC: 238 AN: 5160

South Asian (SAS) AF: 0.0949 AC: 457 AN: 4814

European-Finnish (FIN) AF: 0.222 AC: 2342 AN: 10558

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.183 AC: 12426 AN: 67932

Other (OTH) AF: 0.177 AC: 373 AN: 2102

Alfa AF: 0.174 Hom.: 11044

Bravo AF: 0.159

TwinsUK AF: 0.184 AC: 684

ALSPAC AF: 0.193 AC: 745

ESP6500AA AF: 0.148 AC: 652

ESP6500EA AF: 0.175 AC: 1508

ExAC AF: 0.153 AC: 18532

EpiCase AF: 0.182

EpiControl AF: 0.190

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Familial hypercholesterolemia (3)
-	-	2	Familial hypobetalipoproteinemia 1 (2)
-	-	2	Hypercholesterolemia, autosomal dominant, type B (2)
-	-	2	Hypercholesterolemia, familial, 1 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.6
DANN	Benign	0.92
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.15
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.014
Sift	Benign	0.26	T
Sift4G	Benign	0.34	T
Vest4		0.10
MPC		0.040
ClinPred		0.00044	T
GERP RS		0.15
gMVP		0.26
Mutation Taster		=98/2	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: rs1042031; hg19: chr2-21225753; COSMIC: COSV51923204; COSMIC: COSV51923204;