1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACA

Variant names:

• chr1-161223055-CCACACACA-C
• rs17244502
• NM_001643.2:c.53-13_53-6delTGTGTGTG

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP6_Moderate BS1 BS2_Supporting

The NM_001643.2(APOA2):​c.53-13_53-6delTGTGTGTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,508,324 control chromosomes in the GnomAD database, including 31 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 0)
  • Exomes 𝑓: 0.022 (5 hom.)
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -7 ACMG points.

• BP6: Variant 1-161223055-CCACACACA-C is Benign according to our data. Variant chr1-161223055-CCACACACA-C is described in ClinVar as Benign. ClinVar VariationId is 928702.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1526/147474) while in subpopulation AFR AF = 0.0307 (1225/39930). AF 95% confidence interval is 0.0293. There are 26 homozygotes in GnomAd4. There are 722 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1526 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.53-13_53-6delTGTGTGTG		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.53-13_53-6delTGTGTGTG		splice_region intron	N/A	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.53-13_53-6delTGTGTGTG		splice_region intron	N/A	ENSP00000476740.2	P02652
	APOA2	ENST00000470459.6	TSL:5	c.53-13_53-6delTGTGTGTG		splice_region intron	N/A	ENSP00000477031.1	V9GYS1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1513 AN: 147366 Hom.: 25 Cov.: 0

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00659

Gnomad ASJ AF: 0.000294

Gnomad EAS AF: 0.00585

Gnomad SAS AF: 0.00412

Gnomad FIN AF: 0.000711

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00938

GnomAD2 exomes AF: 0.0527 AC: 10309 AN: 195520 AF XY: 0.0530

Gnomad AFR exome AF: 0.0883

Gnomad AMR exome AF: 0.0569

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.0779

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0424

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0218 AC: 29652 AN: 1360850 Hom.: 5 AF XY: 0.0222 AC XY: 15024 AN XY: 677246

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

African (AFR) AF: 0.0627 AC: 1931 AN: 30806

American (AMR) AF: 0.0443 AC: 1841 AN: 41520

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 621 AN: 24590

East Asian (EAS) AF: 0.0550 AC: 1985 AN: 36068

South Asian (SAS) AF: 0.0351 AC: 2763 AN: 78806

European-Finnish (FIN) AF: 0.0331 AC: 1517 AN: 45812

Middle Eastern (MID) AF: 0.0250 AC: 134 AN: 5360

European-Non Finnish (NFE) AF: 0.0167 AC: 17382 AN: 1041562

Other (OTH) AF: 0.0262 AC: 1478 AN: 56326

⚠️ 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: 0.0103 AC: 1526 AN: 147474 Hom.: 26 Cov.: 0 AF XY: 0.0101 AC XY: 722 AN XY: 71650

African (AFR) AF: 0.0307 AC: 1225 AN: 39930

American (AMR) AF: 0.00658 AC: 98 AN: 14894

Ashkenazi Jewish (ASJ) AF: 0.000294 AC: 1 AN: 3398

East Asian (EAS) AF: 0.00586 AC: 29 AN: 4950

South Asian (SAS) AF: 0.00391 AC: 18 AN: 4608

European-Finnish (FIN) AF: 0.000711 AC: 7 AN: 9852

Middle Eastern (MID) AF: 0.0207 AC: 6 AN: 290

European-Non Finnish (NFE) AF: 0.00185 AC: 123 AN: 66604

Other (OTH) AF: 0.00929 AC: 19 AN: 2046

Alfa AF: 0.0316 Hom.: 197

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

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;