1-161223055-CCACA-C

Position:

• chr1-161223055-CCACA-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6 BS1 BS2_Supporting

The NM_001643.2(APOA2):​c.53-9_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 0.0142 in 1,574,610 control chromosomes in the GnomAD database, including 73 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.021 (71 hom., cov: 0)
  • Exomes 𝑓: 0.013 (2 hom.)
• Consequence: APOA2 NM_001643.2 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• 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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 1-161223055-CCACA-C is Benign according to our data. Variant chr1-161223055-CCACA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293294.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0215 (3170/147586) while in subpopulation AFR AF= 0.0471 (1880/39940). AF 95% confidence interval is 0.0453. There are 71 homozygotes in gnomad4. There are 1521 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 71 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOA2	NM_001643.2	c.53-9_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.53-9_53-6del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001643.2	ENSP00000356969	P1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3158 AN: 147472 Hom.: 71 Cov.: 0

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.00556

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00206

Gnomad EAS AF: 0.0292

Gnomad SAS AF: 0.0154

Gnomad FIN AF: 0.00383

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0217

GnomAD4 exome AF: 0.0134 AC: 19122 AN: 1427024 Hom.: 2 AF XY: 0.0134 AC XY: 9547 AN XY: 710292

Gnomad4 AFR exome AF: 0.0500

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.00582

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0155

GnomAD4 genome AF: 0.0215 AC: 3170 AN: 147586 Hom.: 71 Cov.: 0 AF XY: 0.0212 AC XY: 1521 AN XY: 71692

Gnomad4 AFR AF: 0.0471

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.00206

Gnomad4 EAS AF: 0.0293

Gnomad4 SAS AF: 0.0158

Gnomad4 FIN AF: 0.00383

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0229

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2019	Variant summary: APOA2 c.53-9_53-6delTGTG 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 0.022 in 28768 control chromosomes, predominantly at a frequency of 0.049 within the African or African-American subpopulation in the gnomAD database, including 24 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2450-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 African or African-American origin. The variant was reported to co-occur with a pathogenic LDLR variant. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Apolipoprotein A-II deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

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;