1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACACACA

Variant names:

• chr1-161223055-CCACA-C
• rs17244502
• NM_001643.2:c.53-9_53-6delTGTG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6 BS1 BS2_Supporting

The NM_001643.2(APOA2):​c.53-9_53-6delTGTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 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, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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: Likely_benign. The variant received -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 VariationId is 293294.
• 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3170 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.53-9_53-6delTGTG		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.53-9_53-6delTGTG		splice_region intron	N/A	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.53-9_53-6delTGTG		splice_region intron	N/A	ENSP00000476740.2	P02652
	APOA2	ENST00000470459.6	TSL:5	c.53-9_53-6delTGTG		splice_region intron	N/A	ENSP00000477031.1	V9GYS1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0500 AC: 1634 AN: 32660

American (AMR) AF: 0.0154 AC: 677 AN: 43830

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 99 AN: 25570

East Asian (EAS) AF: 0.0312 AC: 1217 AN: 38992

South Asian (SAS) AF: 0.0145 AC: 1229 AN: 84866

European-Finnish (FIN) AF: 0.00582 AC: 278 AN: 47762

Middle Eastern (MID) AF: 0.0121 AC: 68 AN: 5600

European-Non Finnish (NFE) AF: 0.0119 AC: 13003 AN: 1088712

Other (OTH) AF: 0.0155 AC: 917 AN: 59032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0471 AC: 1880 AN: 39940

American (AMR) AF: 0.0160 AC: 238 AN: 14896

Ashkenazi Jewish (ASJ) AF: 0.00206 AC: 7 AN: 3402

East Asian (EAS) AF: 0.0293 AC: 145 AN: 4954

South Asian (SAS) AF: 0.0158 AC: 73 AN: 4608

European-Finnish (FIN) AF: 0.00383 AC: 38 AN: 9912

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0110 AC: 735 AN: 66634

Other (OTH) AF: 0.0229 AC: 47 AN: 2048

Alfa AF: 0.00410 Hom.: 197

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	-	APOLIPOPROTEIN A-II DEFICIENCY (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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

Other links and lift over

dbSNP: rs17244502; hg19: chr1-161192845;