rs76202659

Variant names:

• chr2-21030027-G-A
• rs76202659
• NM_000384.3:c.1353-12C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000384.3(APOB):​c.1353-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,551,580 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (40 hom.)
• Consequence: APOB NM_000384.3 intron
• Scores: Splicing: ADA: 0.00008316
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.0720
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-21030027-G-A is Benign according to our data. Variant chr2-21030027-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265880.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1997/152312) while in subpopulation AFR AF = 0.0456 (1895/41556). AF 95% confidence interval is 0.0439. There are 40 homozygotes in GnomAd4. There are 946 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	NM_000384.3	MANE Select	c.1353-12C>T		intron	N/A	NP_000375.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOB	ENST00000233242.5	TSL:1 MANE Select	c.1353-12C>T		intron	N/A	ENSP00000233242.1
	APOB	ENST00000399256.4	TSL:1	c.1353-12C>T		intron	N/A	ENSP00000382200.4
	APOB	ENST00000673739.2		n.*659-12C>T		intron	N/A	ENSP00000501110.2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1990 AN: 152194 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00372 AC: 934 AN: 251290 AF XY: 0.00265

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00154 AC: 2152 AN: 1399268 Hom.: 40 Cov.: 24 AF XY: 0.00141 AC XY: 984 AN XY: 700330

African (AFR) AF: 0.0496 AC: 1592 AN: 32112

American (AMR) AF: 0.00262 AC: 117 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00190 AC: 49 AN: 25726

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39394

South Asian (SAS) AF: 0.000435 AC: 37 AN: 85006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00389 AC: 22 AN: 5654

European-Non Finnish (NFE) AF: 0.000100 AC: 106 AN: 1054980

Other (OTH) AF: 0.00390 AC: 228 AN: 58418

GnomAD4 genome AF: 0.0131 AC: 1997 AN: 152312 Hom.: 40 Cov.: 33 AF XY: 0.0127 AC XY: 946 AN XY: 74492

African (AFR) AF: 0.0456 AC: 1895 AN: 41556

American (AMR) AF: 0.00314 AC: 48 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68026

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00945 Hom.: 17

Bravo AF: 0.0148

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Hypercholesterolemia, familial, 1 (2)
-	-	2	not provided (2)
-	-	1	Familial hypobetalipoproteinemia 1 (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
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		-0.072
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000083
dbscSNV1_RF	Benign	0.0
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: rs76202659; hg19: chr2-21252899;