1-161223055-CCACACACACA-C

Position:

• chr1-161223055-CCACACACACA-C

Variant summary

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

The ENST00000367990.7(APOA2):​c.53-15_53-6delTGTGTGTGTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,434,990 control chromosomes in the GnomAD database, including 1,176 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (992 hom., cov: 0)
  • Exomes 𝑓: 0.13 (1176 hom.)
  • Failed GnomAD Quality Control
• Consequence: APOA2 ENST00000367990.7 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:4
• 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]

APOA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 1-161223055-CCACACACACA-C is Benign according to our data. Variant chr1-161223055-CCACACACACA-C is described in ClinVar as [Benign]. Clinvar id is 929172.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161223055-CCACACACACA-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOA2	NM_001643.2	c.53-15_53-6delTGTGTGTGTG		splice_region_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.53-15_53-6delTGTGTGTGTG		splice_region_variant, intron_variant		1	NM_001643.2	ENSP00000356969.3
APOA2	ENST00000470459.6	c.53-15_53-6delTGTGTGTGTG		splice_region_variant, intron_variant		5		ENSP00000477031.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16037 AN: 147468 Hom.: 988 Cov.: 0

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0570

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.135 AC: 26380 AN: 195520 Hom.: 227 AF XY: 0.137 AC XY: 14659 AN XY: 106664

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.0585

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.127 AC: 182324 AN: 1434990 Hom.: 1176 AF XY: 0.127 AC XY: 90994 AN XY: 713994

Gnomad4 AFR exome AF: 0.0486

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.0574

Gnomad4 EAS exome AF: 0.188

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.109 AC: 16052 AN: 147580 Hom.: 992 Cov.: 0 AF XY: 0.109 AC XY: 7847 AN XY: 71700

Gnomad4 AFR AF: 0.0518

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0570

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.106

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2019	Variant summary: APOA2 c.53-15_53-6delTGTGTGTGTG 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 0.13 in 195520 control chromosomes, predominantly at a frequency of 0.18 within the East Asian subpopulation in the gnomAD database, including 17 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 9000-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. The variant is located in a highly polymorphic region consisting of a run of TG dinucleotide sequences. 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

APOA2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

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). -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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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;