2-21028042-G-A

Variant names:

• chr2-21028042-G-A
• rs679899
• NM_000384.3:c.1853C>T

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.1853C>T​(p.Ala618Val) variant causes a missense change. The variant allele was found at a frequency of 0.47 in 1,608,604 control chromosomes in the GnomAD database, including 187,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (14276 hom., cov: 32)
  • Exomes 𝑓: 0.48 (172976 hom.)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 6.75
• Publications: 100 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0775246E-6).
• BP6: Variant 2-21028042-G-A is Benign according to our data. Variant chr2-21028042-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.832 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.1853C>T	p.Ala618Val	missense	Exon 14 of 29	NP_000375.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.1853C>T	p.Ala618Val	missense	Exon 14 of 29	ENSP00000233242.1
	APOB	ENST00000399256.4	TSL:1	c.1853C>T	p.Ala618Val	missense	Exon 14 of 17	ENSP00000382200.4
	APOB	ENST00000673739.2		n.*1159C>T		non_coding_transcript_exon	Exon 13 of 25	ENSP00000501110.2

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60939 AN: 151950 Hom.: 14286 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.421

GnomAD2 exomes AF: 0.490 AC: 123023 AN: 251266 AF XY: 0.501

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.395

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.852

Gnomad FIN exome AF: 0.568

Gnomad NFE exome AF: 0.469

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.477 AC: 694384 AN: 1456536 Hom.: 172976 Cov.: 35 AF XY: 0.482 AC XY: 349457 AN XY: 724912

African (AFR) AF: 0.159 AC: 5308 AN: 33404

American (AMR) AF: 0.390 AC: 17442 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 9652 AN: 26116

East Asian (EAS) AF: 0.863 AC: 34245 AN: 39664

South Asian (SAS) AF: 0.610 AC: 52510 AN: 86122

European-Finnish (FIN) AF: 0.558 AC: 29791 AN: 53402

Middle Eastern (MID) AF: 0.457 AC: 2628 AN: 5752

European-Non Finnish (NFE) AF: 0.465 AC: 514456 AN: 1107122

Other (OTH) AF: 0.471 AC: 28352 AN: 60240

GnomAD4 genome AF: 0.401 AC: 60920 AN: 152068 Hom.: 14276 Cov.: 32 AF XY: 0.410 AC XY: 30508 AN XY: 74332

African (AFR) AF: 0.174 AC: 7231 AN: 41492

American (AMR) AF: 0.377 AC: 5760 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1289 AN: 3468

East Asian (EAS) AF: 0.853 AC: 4410 AN: 5172

South Asian (SAS) AF: 0.624 AC: 3010 AN: 4820

European-Finnish (FIN) AF: 0.571 AC: 6040 AN: 10572

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31848 AN: 67946

Other (OTH) AF: 0.424 AC: 894 AN: 2110

Alfa AF: 0.454 Hom.: 74810

Bravo AF: 0.372

TwinsUK AF: 0.460 AC: 1706

ALSPAC AF: 0.475 AC: 1829

ESP6500AA AF: 0.177 AC: 779

ESP6500EA AF: 0.462 AC: 3975

ExAC AF: 0.485 AC: 58942

Asia WGS AF: 0.694 AC: 2411 AN: 3478

EpiCase AF: 0.470

EpiControl AF: 0.469

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Hypercholesterolemia, familial, 1 (4)
-	-	2	Familial hypercholesterolemia (2)
-	-	2	Familial hypobetalipoproteinemia 1 (2)
-	-	2	Hypercholesterolemia, autosomal dominant, type B (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)
-	-	1	not provided (1)
-	-	-	Warfarin response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.079	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.93	T
PhyloP100		6.7
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Vest4		0.55
MPC		0.27
ClinPred		0.016	T
GERP RS		5.7
gMVP		0.68
Mutation Taster		=65/35	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs679899; hg19: chr2-21250914; COSMIC: COSV107231950; COSMIC: COSV107231950;