1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACACACACA

Variant names:

• chr1-161223055-CCA-C
• rs17244502
• NM_001643.2:c.53-7_53-6delTG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001643.2(APOA2):​c.53-7_53-6delTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,529,804 control chromosomes in the GnomAD database, including 230 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (215 hom., cov: 0)
  • Exomes 𝑓: 0.047 (15 hom.)
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.116

Genes affected

APOA2 (HGNC:601): (apolipoprotein A2) This gene encodes apolipoprotein (apo-) A-II, which is the second most abundant protein of the high density lipoprotein particles. The protein is found in plasma as a monomer, homodimer, or heterodimer with apolipoprotein D. Defects in this gene may result in apolipoprotein A-II deficiency or hypercholesterolemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 1-161223055-CCA-C is Benign according to our data. Variant chr1-161223055-CCA-C is described in ClinVar as [Benign]. Clinvar id is 933213.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161223055-CCA-C is described in Lovd as [Likely_benign]. Variant chr1-161223055-CCA-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA2	NM_001643.2	c.53-7_53-6delTG		splice_region_variant, intron_variant	Intron 2 of 3	ENST00000367990.7	NP_001634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA2	ENST00000367990.7	c.53-7_53-6delTG		splice_region_variant, intron_variant	Intron 2 of 3	1	NM_001643.2	ENSP00000356969.3
APOA2	ENST00000470459.6	c.53-7_53-6delTG		splice_region_variant, intron_variant	Intron 2 of 4	5		ENSP00000477031.1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5675 AN: 147392 Hom.: 214 Cov.: 0

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.00443

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00282

Gnomad SAS AF: 0.0646

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0286

GnomAD3 exomes AF: 0.0600 AC: 11738 AN: 195520 Hom.: 67 AF XY: 0.0626 AC XY: 6682 AN XY: 106664

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0652

Gnomad EAS exome AF: 0.00651

Gnomad SAS exome AF: 0.0837

Gnomad FIN exome AF: 0.0503

Gnomad NFE exome AF: 0.0654

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0467 AC: 64519 AN: 1382304 Hom.: 15 AF XY: 0.0478 AC XY: 32904 AN XY: 688372

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0533

Gnomad4 EAS exome AF: 0.00304

Gnomad4 SAS exome AF: 0.0764

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0452

Gnomad4 OTH exome AF: 0.0460

GnomAD4 genome AF: 0.0386 AC: 5690 AN: 147500 Hom.: 215 Cov.: 0 AF XY: 0.0388 AC XY: 2780 AN XY: 71658

Gnomad4 AFR AF: 0.0909

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00282

Gnomad4 SAS AF: 0.0654

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.0164

Gnomad4 OTH AF: 0.0283

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 29, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APOA2 c.53-7_53-6delTG alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.06 in 195520 control chromosomes, predominantly at a frequency of 0.12 within the African or African-American subpopulation in the gnomAD database, including 28 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6000 fold of the estimated maximal expected allele frequency for a pathogenic variant in APOA2 causing Early Onset Coronary Artery Disease phenotype (2e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.53-7_53-6delTG in individuals affected with Early Onset Coronary Artery Disease and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

APOA2-related disorder Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs17244502; hg19: chr1-161192845;