2-21038082-C-T

Position:

• chr2-21038082-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000384.3(APOB):​c.413G>A​(p.Gly138Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APOB NM_000384.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOB	NM_000384.3	c.413G>A	p.Gly138Glu	missense_variant	5/29	ENST00000233242.5	NP_000375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOB	ENST00000233242.5	c.413G>A	p.Gly138Glu	missense_variant	5/29	1	NM_000384.3	ENSP00000233242	P1
APOB	ENST00000399256.4	c.413G>A	p.Gly138Glu	missense_variant	5/17	1		ENSP00000382200
APOB	ENST00000673739.2	c.384-827G>A		intron_variant, NMD_transcript_variant				ENSP00000501110
APOB	ENST00000673882.2	c.384-827G>A		intron_variant, NMD_transcript_variant				ENSP00000501253

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251488 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 28, 2018

This sequence change replaces glycine with glutamic acid at codon 138 of the APOB protein (p.Gly138Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs776319722, ExAC 0.01%). This variant has not been reported in the literature in individuals with APOB-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.00050	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.24	T;T
Sift4G	Uncertain	0.0050	D;D
Vest4		0.50
MutPred		0.89		Gain of solvent accessibility (P = 0.0145);Gain of solvent accessibility (P = 0.0145);
MVP		0.85
MPC		0.28
ClinPred		0.93	D
GERP RS		5.7
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs776319722; hg19: chr2-21260954; COSMIC: COSV51944767;