1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACACA

Variant names:

• chr1-161223055-CCACACA-C
• rs17244502
• NM_001643.2:c.53-11_53-6delTGTGTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001643.2(APOA2):​c.53-11_53-6delTGTGTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.32 (7601 hom., cov: 0)
  • Exomes 𝑓: 0.26 (2653 hom.)
  • Failed GnomAD Quality Control
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.116
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• apolipoprotein A-II amyloidosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 1-161223055-CCACACA-C is Benign according to our data. Variant chr1-161223055-CCACACA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 293295.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001643.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA2	NM_001643.2	MANE Select	c.53-11_53-6delTGTGTG		splice_region intron	N/A	NP_001634.1	P02652

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA2	ENST00000367990.7	TSL:1 MANE Select	c.53-11_53-6delTGTGTG		splice_region intron	N/A	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.53-11_53-6delTGTGTG		splice_region intron	N/A	ENSP00000476740.2	P02652
	APOA2	ENST00000470459.6	TSL:5	c.53-11_53-6delTGTGTG		splice_region intron	N/A	ENSP00000477031.1	V9GYS1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 47590 AN: 147306 Hom.: 7589 Cov.: 0

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.327

GnomAD2 exomes AF: 0.282 AC: 55088 AN: 195520 AF XY: 0.283

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.270

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.264 AC: 378883 AN: 1435404 Hom.: 2653 AF XY: 0.264 AC XY: 188776 AN XY: 713980

African (AFR) AF: 0.296 AC: 9764 AN: 32948

American (AMR) AF: 0.295 AC: 12878 AN: 43610

Ashkenazi Jewish (ASJ) AF: 0.266 AC: 6813 AN: 25656

East Asian (EAS) AF: 0.326 AC: 12652 AN: 38810

South Asian (SAS) AF: 0.299 AC: 25389 AN: 85034

European-Finnish (FIN) AF: 0.279 AC: 13310 AN: 47716

Middle Eastern (MID) AF: 0.286 AC: 1603 AN: 5612

European-Non Finnish (NFE) AF: 0.256 AC: 280347 AN: 1096724

Other (OTH) AF: 0.272 AC: 16127 AN: 59294

GnomAD4 genome AF: 0.323 AC: 47636 AN: 147418 Hom.: 7601 Cov.: 0 AF XY: 0.327 AC XY: 23426 AN XY: 71626

African (AFR) AF: 0.343 AC: 13697 AN: 39894

American (AMR) AF: 0.338 AC: 5022 AN: 14876

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1096 AN: 3398

East Asian (EAS) AF: 0.399 AC: 1971 AN: 4946

South Asian (SAS) AF: 0.378 AC: 1740 AN: 4600

European-Finnish (FIN) AF: 0.352 AC: 3488 AN: 9900

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.294 AC: 19590 AN: 66568

Other (OTH) AF: 0.331 AC: 676 AN: 2042

Alfa AF: 0.250 Hom.: 197

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	APOA2-related disorder (1)
-	1	-	APOLIPOPROTEIN A-II DEFICIENCY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17244502; hg19: chr1-161192845;