2-21009931-T-C

Variant names:

• chr2-21009931-T-C
• rs584542
• NM_000384.3:c.6937A>G

Variant summary

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

The ENST00000233242.5(APOB):​c.6937A>G​(p.Ile2313Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,613,922 control chromosomes in the GnomAD database, including 801,973 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2313M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.98 (73909 hom., cov: 33)
  • Exomes 𝑓: 1.0 (728064 hom.)
• Consequence: APOB ENST00000233242.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.238
• Publications: 43 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=1.881807E-6).
• BP6: Variant 2-21009931-T-C is Benign according to our data. Variant chr2-21009931-T-C is described in ClinVar as Benign. ClinVar VariationId is 1168905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.993 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.6937A>G	p.Ile2313Val	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.6937A>G	p.Ile2313Val	missense	Exon 26 of 29	ENSP00000233242.1

Frequencies

GnomAD3 genomes AF: 0.985 AC: 149910 AN: 152224 Hom.: 73850 Cov.: 33

Gnomad AFR AF: 0.947

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.987

GnomAD2 exomes AF: 0.996 AC: 250044 AN: 251108 AF XY: 0.997

Gnomad AFR exome AF: 0.947

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1458786 AN: 1461580 Hom.: 728064 Cov.: 53 AF XY: 0.998 AC XY: 725876 AN XY: 727098

African (AFR) AF: 0.941 AC: 31495 AN: 33460

American (AMR) AF: 0.997 AC: 44587 AN: 44722

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26122 AN: 26122

East Asian (EAS) AF: 1.00 AC: 39645 AN: 39658

South Asian (SAS) AF: 1.00 AC: 86209 AN: 86250

European-Finnish (FIN) AF: 1.00 AC: 53390 AN: 53390

Middle Eastern (MID) AF: 0.993 AC: 5724 AN: 5766

European-Non Finnish (NFE) AF: 1.00 AC: 1111467 AN: 1111832

Other (OTH) AF: 0.996 AC: 60147 AN: 60380

GnomAD4 genome AF: 0.985 AC: 150027 AN: 152342 Hom.: 73909 Cov.: 33 AF XY: 0.985 AC XY: 73377 AN XY: 74490

African (AFR) AF: 0.948 AC: 39388 AN: 41566

American (AMR) AF: 0.995 AC: 15232 AN: 15302

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5175 AN: 5182

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68013 AN: 68044

Other (OTH) AF: 0.987 AC: 2087 AN: 2114

Alfa AF: 0.995 Hom.: 167275

Bravo AF: 0.983

TwinsUK AF: 0.999 AC: 3706

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.947 AC: 4172

ESP6500EA AF: 0.999 AC: 8595

ExAC AF: 0.995 AC: 120801

Asia WGS AF: 0.997 AC: 3467 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 0.999

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.041
DANN	Benign	0.19
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.24
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.014
Sift	Benign	0.63	T
Sift4G	Benign	0.64	T
Vest4		0.032
MPC		0.033
ClinPred		0.00047	T
GERP RS		-3.8
gMVP		0.17
Mutation Taster		=95/5	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: rs584542; hg19: chr2-21232803; COSMIC: COSV107231948;