1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACACACACA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001643.2(APOA2):​c.53-7_53-6delTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0459 in 1,529,804 control chromosomes in the GnomAD database, including 230 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (215 hom., cov: 0)
  • Exomes 𝑓: 0.047 (15 hom.)
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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 -10 ACMG points.

• BP6: Variant 1-161223055-CCA-C is Benign according to our data. Variant chr1-161223055-CCA-C is described in ClinVar as Benign. ClinVar VariationId is 933213.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 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.53-7_53-6delTG		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.53-7_53-6delTG		splice_region intron	N/A	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.53-7_53-6delTG		splice_region intron	N/A	ENSP00000476740.2	P02652
	APOA2	ENST00000470459.6	TSL:5	c.53-7_53-6delTG		splice_region intron	N/A	ENSP00000477031.1	V9GYS1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5675 AN: 147392 Hom.: 214 Cov.: 0

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.00443

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00282

Gnomad SAS AF: 0.0646

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0286

GnomAD2 exomes AF: 0.0600 AC: 11738 AN: 195520 AF XY: 0.0626

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0652

Gnomad EAS exome AF: 0.00651

Gnomad FIN exome AF: 0.0503

Gnomad NFE exome AF: 0.0654

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0467 AC: 64519 AN: 1382304 Hom.: 15 AF XY: 0.0478 AC XY: 32904 AN XY: 688372

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

African (AFR) AF: 0.104 AC: 3317 AN: 31950

American (AMR) AF: 0.0232 AC: 1009 AN: 43458

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 1329 AN: 24952

East Asian (EAS) AF: 0.00304 AC: 119 AN: 39090

South Asian (SAS) AF: 0.0764 AC: 6383 AN: 83532

European-Finnish (FIN) AF: 0.0420 AC: 1966 AN: 46774

Middle Eastern (MID) AF: 0.0621 AC: 339 AN: 5460

European-Non Finnish (NFE) AF: 0.0452 AC: 47407 AN: 1049472

Other (OTH) AF: 0.0460 AC: 2650 AN: 57616

⚠️ 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: 0.0386 AC: 5690 AN: 147500 Hom.: 215 Cov.: 0 AF XY: 0.0388 AC XY: 2780 AN XY: 71658

African (AFR) AF: 0.0909 AC: 3629 AN: 39914

American (AMR) AF: 0.0211 AC: 314 AN: 14894

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 80 AN: 3396

East Asian (EAS) AF: 0.00282 AC: 14 AN: 4958

South Asian (SAS) AF: 0.0654 AC: 301 AN: 4602

European-Finnish (FIN) AF: 0.0184 AC: 182 AN: 9886

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0164 AC: 1093 AN: 66608

Other (OTH) AF: 0.0283 AC: 58 AN: 2048

Alfa AF: 0.0397 Hom.: 197

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	APOA2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

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;