1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACACACACACACA

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP6_Very_Strong BS1 BS2_Supporting

The NM_001643.2(APOA2):​c.53-7_53-6dupTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (83 hom., cov: 0)
  • Exomes 𝑓: 0.032 (5 hom.)
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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 -13 ACMG points.

• BP6: Variant 1-161223055-C-CCA is Benign according to our data. Variant chr1-161223055-C-CCA is described in ClinVar as [Benign]. Clinvar id is 774279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0321 (4733/147584) while in subpopulation NFE AF= 0.0388 (2588/66630). AF 95% confidence interval is 0.0376. There are 83 homozygotes in gnomad4. There are 2300 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 83 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 rank	MANE	Protein	UniProt
APOA2	NM_001643.2	c.53-7_53-6dupTG		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_53-6dupTG		splice_region_variant, intron_variant	Intron 2 of 3	1	NM_001643.2	ENSP00000356969.3
APOA2	ENST00000470459.6	c.53-7_53-6dupTG		splice_region_variant, intron_variant	Intron 2 of 4	5		ENSP00000477031.1

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4735 AN: 147472 Hom.: 83 Cov.: 0

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0443

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00866

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.0543

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.0323 AC: 46216 AN: 1430914 Hom.: 5 Cov.: 0 AF XY: 0.0321 AC XY: 22830 AN XY: 712064

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.0280

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.00816

Gnomad4 SAS exome AF: 0.0223

Gnomad4 FIN exome AF: 0.0451

Gnomad4 NFE exome AF: 0.0343

Gnomad4 OTH exome AF: 0.0294

GnomAD4 genome AF: 0.0321 AC: 4733 AN: 147584 Hom.: 83 Cov.: 0 AF XY: 0.0321 AC XY: 2300 AN XY: 71702

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.0342

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.00868

Gnomad4 SAS AF: 0.0206

Gnomad4 FIN AF: 0.0543

Gnomad4 NFE AF: 0.0388

Gnomad4 OTH AF: 0.0308

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 23, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Nov 06, 2019

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_53-6dupTG 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 0.036 in 28768 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 1823-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 benign. Co-occurrences with other pathogenic variant(s) have been reported (LDLR c.1567G>A, p.Val523Met). 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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;