1-161223055-CCACACACACACA-C

Position:

• chr1-161223055-CCACACACACACA-C

Variant summary

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

The NM_001643.2(APOA2):​c.53-17_53-6del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,423,886 control chromosomes in the GnomAD database, including 2,403 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1802 hom., cov: 0)
  • Exomes 𝑓: 0.15 (2403 hom.)
  • Failed GnomAD Quality Control
• Consequence: APOA2 NM_001643.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.506

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-CCACACACACACA-C is Benign according to our data. Variant chr1-161223055-CCACACACACACA-C is described in ClinVar as [Benign]. Clinvar id is 928640.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOA2	NM_001643.2	c.53-17_53-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000367990.7	NP_001634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOA2	ENST00000367990.7	c.53-17_53-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001643.2	ENSP00000356969	P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22251 AN: 147474 Hom.: 1803 Cov.: 0

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0953

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.161

GnomAD3 exomes AF: 0.177 AC: 34517 AN: 195520 Hom.: 491 AF XY: 0.172 AC XY: 18299 AN XY: 106664

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.273

Gnomad SAS exome AF: 0.135

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.149 AC: 211500 AN: 1423886 Hom.: 2403 AF XY: 0.147 AC XY: 104475 AN XY: 708466

Gnomad4 AFR exome AF: 0.0956

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.193

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.151 AC: 22243 AN: 147584 Hom.: 1802 Cov.: 0 AF XY: 0.151 AC XY: 10801 AN XY: 71700

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.160

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Aug 13, 2019

Variant summary: APOA2 c.53-17_53-6delTGTGTGTGTGTG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 0.18 in 195520 control chromosomes, predominantly at a frequency of 0.27 within the East Asian subpopulation in the gnomAD database, including 85 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 13500-folds over 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 East Asian origin. To our knowledge, no occurrence of c.53-17_53-6delTGTGTGTGTGTG 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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;