2-21043902-GGCAGCGCCA-G

Variant names:

• chr2-21043902-GGCAGCGCCA-G
• rs17240441
• NM_000384.3:c.35_43delTGGCGCTGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000384.3(APOB):​c.35_43delTGGCGCTGC​(p.Leu12_Leu14del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,424,858 control chromosomes in the GnomAD database, including 69,415 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L12L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5880 hom., cov: 20)
  • Exomes 𝑓: 0.31 (63535 hom.)
• Consequence: APOB NM_000384.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:14
• Conservation: PhyloP100: 2.29
• Publications: 33 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

ENSG00000299295 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-21043902-GGCAGCGCCA-G is Benign according to our data. Variant chr2-21043902-GGCAGCGCCA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.32 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.35_43delTGGCGCTGC	p.Leu12_Leu14del	disruptive_inframe_deletion	Exon 1 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.35_43delTGGCGCTGC	p.Leu12_Leu14del	disruptive_inframe_deletion	Exon 1 of 29	ENSP00000233242.1	P04114
	APOB	ENST00000399256.4	TSL:1	c.35_43delTGGCGCTGC	p.Leu12_Leu14del	disruptive_inframe_deletion	Exon 1 of 17	ENSP00000382200.4	A8MUN2
	APOB	ENST00000673739.2		n.35_43delTGGCGCTGC		non_coding_transcript_exon	Exon 1 of 25	ENSP00000501110.2	A0A669KB70

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41523 AN: 151310 Hom.: 5870 Cov.: 20

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.122 AC: 6596 AN: 54138 AF XY: 0.122

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.0843

Gnomad EAS exome AF: 0.0486

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.307 AC: 390913 AN: 1273442 Hom.: 63535 AF XY: 0.302 AC XY: 189368 AN XY: 626708

African (AFR) AF: 0.187 AC: 4751 AN: 25350

American (AMR) AF: 0.297 AC: 6239 AN: 21042

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 4175 AN: 21176

East Asian (EAS) AF: 0.190 AC: 5203 AN: 27422

South Asian (SAS) AF: 0.149 AC: 9959 AN: 66768

European-Finnish (FIN) AF: 0.273 AC: 8605 AN: 31512

Middle Eastern (MID) AF: 0.201 AC: 762 AN: 3790

European-Non Finnish (NFE) AF: 0.329 AC: 336725 AN: 1024254

Other (OTH) AF: 0.278 AC: 14494 AN: 52128

GnomAD4 genome AF: 0.275 AC: 41577 AN: 151416 Hom.: 5880 Cov.: 20 AF XY: 0.271 AC XY: 20029 AN XY: 74010

African (AFR) AF: 0.209 AC: 8643 AN: 41414

American (AMR) AF: 0.328 AC: 4977 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 744 AN: 3470

East Asian (EAS) AF: 0.202 AC: 1036 AN: 5134

South Asian (SAS) AF: 0.151 AC: 731 AN: 4826

European-Finnish (FIN) AF: 0.274 AC: 2863 AN: 10430

Middle Eastern (MID) AF: 0.186 AC: 54 AN: 290

European-Non Finnish (NFE) AF: 0.321 AC: 21699 AN: 67650

Other (OTH) AF: 0.255 AC: 536 AN: 2106

Alfa AF: 0.111 Hom.: 175

Bravo AF: 0.280

Asia WGS AF: 0.184 AC: 634 AN: 3440

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Hypercholesterolemia, familial, 1 (3)
-	-	2	Familial hypercholesterolemia (2)
-	1	1	not provided (2)
-	-	1	APOB POLYMORPHISM IN SIGNAL PEPTIDE (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypercholesterolemia, autosomal dominant, type B;C4551990:Familial hypobetalipoproteinemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=186/14	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17240441; hg19: chr2-21266774; COSMIC: COSV51932888;