rs1801700

Variant names:

• chr2-21022941-G-A
• rs1801700
• NM_000384.3:c.2706C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-21022941-G-A
• chr2-21022941-G-C
• chr2-21022941-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000384.3(APOB):​c.2706C>T​(p.Asn902Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,614,096 control chromosomes in the GnomAD database, including 1,944 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 0.035 (143 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1801 hom.)
• Consequence: APOB NM_000384.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 1.74
• Publications: 22 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-21022941-G-A is Benign according to our data. Variant chr2-21022941-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255981.
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0511 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.2706C>T	p.Asn902Asn	synonymous	Exon 18 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.2706C>T	p.Asn902Asn	synonymous	Exon 18 of 29	ENSP00000233242.1	P04114
	APOB	ENST00000673739.2		n.*2012C>T		non_coding_transcript_exon	Exon 17 of 25	ENSP00000501110.2	A0A669KB70
	APOB	ENST00000673882.2		n.*2012C>T		non_coding_transcript_exon	Exon 17 of 23	ENSP00000501253.2	A0A669KB70

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5383 AN: 152128 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.00804

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0681

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0354 AC: 8898 AN: 251400 AF XY: 0.0363

Gnomad AFR exome AF: 0.00849

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0465 AC: 68032 AN: 1461850 Hom.: 1801 Cov.: 32 AF XY: 0.0461 AC XY: 33528 AN XY: 727228

African (AFR) AF: 0.00753 AC: 252 AN: 33480

American (AMR) AF: 0.0193 AC: 862 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 711 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0250 AC: 2155 AN: 86258

European-Finnish (FIN) AF: 0.0593 AC: 3170 AN: 53420

Middle Eastern (MID) AF: 0.0215 AC: 124 AN: 5766

European-Non Finnish (NFE) AF: 0.0527 AC: 58552 AN: 1111972

Other (OTH) AF: 0.0364 AC: 2201 AN: 60396

GnomAD4 genome AF: 0.0354 AC: 5385 AN: 152246 Hom.: 143 Cov.: 32 AF XY: 0.0358 AC XY: 2668 AN XY: 74454

African (AFR) AF: 0.00802 AC: 333 AN: 41540

American (AMR) AF: 0.0263 AC: 403 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4820

European-Finnish (FIN) AF: 0.0681 AC: 722 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0525 AC: 3570 AN: 68004

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.0448 Hom.: 365

Bravo AF: 0.0308

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0489

EpiControl AF: 0.0509

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.5
DANN	Benign	0.82
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs1801700; hg19: chr2-21245813;