chr1-161223055-CCACACACACACACA-C

Variant names:

• chr1-161223055-CCACACACACACACA-C
• rs17244502
• NM_001643.2:c.53-19_53-6delTGTGTGTGTGTGTG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_001643.2(APOA2):​c.53-19_53-6delTGTGTGTGTGTGTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,565,692 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0025 (0 hom.)
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.506
• 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 -1 ACMG points.

• BS2: High AC in GnomAd4 at 63 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.53-19_53-6delTGTGTGTGTGTGTG		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.53-19_53-6delTGTGTGTGTGTGTG		splice_region intron	N/A	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.53-19_53-6delTGTGTGTGTGTGTG		splice_region intron	N/A	ENSP00000476740.2	P02652
	APOA2	ENST00000470459.6	TSL:5	c.53-19_53-6delTGTGTGTGTGTGTG		splice_region intron	N/A	ENSP00000477031.1	V9GYS1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 63 AN: 147516 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000753

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00101

Gnomad ASJ AF: 0.00588

Gnomad EAS AF: 0.000403

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000285

Gnomad OTH AF: 0.00148

GnomAD2 exomes AF: 0.00977 AC: 1911 AN: 195520 AF XY: 0.00898

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.0192

Gnomad FIN exome AF: 0.00663

Gnomad NFE exome AF: 0.00830

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00250 AC: 3547 AN: 1418064 Hom.: 0 AF XY: 0.00247 AC XY: 1746 AN XY: 705530

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

African (AFR) AF: 0.00125 AC: 41 AN: 32902

American (AMR) AF: 0.0114 AC: 484 AN: 42412

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 302 AN: 25132

East Asian (EAS) AF: 0.00907 AC: 340 AN: 37466

South Asian (SAS) AF: 0.00219 AC: 185 AN: 84390

European-Finnish (FIN) AF: 0.00378 AC: 180 AN: 47618

Middle Eastern (MID) AF: 0.00415 AC: 23 AN: 5548

European-Non Finnish (NFE) AF: 0.00167 AC: 1806 AN: 1084094

Other (OTH) AF: 0.00318 AC: 186 AN: 58502

⚠️ 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: 0.000427 AC: 63 AN: 147628 Hom.: 0 Cov.: 0 AF XY: 0.000349 AC XY: 25 AN XY: 71726

African (AFR) AF: 0.0000751 AC: 3 AN: 39956

American (AMR) AF: 0.00101 AC: 15 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.00588 AC: 20 AN: 3402

East Asian (EAS) AF: 0.000403 AC: 2 AN: 4958

South Asian (SAS) AF: 0.000217 AC: 1 AN: 4608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000285 AC: 19 AN: 66642

Other (OTH) AF: 0.00146 AC: 3 AN: 2048

Alfa AF: 0.0123 Hom.: 197

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism

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;