chr1-161223055-C-CCA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP6_Very_Strong BS1 BS2_Supporting

The NM_001643.2(APOA2):​c.53-7_53-6dupTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (83 hom., cov: 0)
  • Exomes 𝑓: 0.032 (5 hom.)
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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 -13 ACMG points.

• BP6: Variant 1-161223055-C-CCA is Benign according to our data. Variant chr1-161223055-C-CCA is described in ClinVar as Benign. ClinVar VariationId is 774279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0321 (4733/147584) while in subpopulation NFE AF = 0.0388 (2588/66630). AF 95% confidence interval is 0.0376. There are 83 homozygotes in GnomAd4. There are 2300 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4733 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.53-7_53-6dupTG		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_53-6dupTG		splice_region intron	N/A	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.53-7_53-6dupTG		splice_region intron	N/A	ENSP00000476740.2	P02652
	APOA2	ENST00000470459.6	TSL:5	c.53-7_53-6dupTG		splice_region intron	N/A	ENSP00000477031.1	V9GYS1

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4735 AN: 147472 Hom.: 83 Cov.: 0

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.0443

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00866

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.0543

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0311

GnomAD4 exome AF: 0.0323 AC: 46216 AN: 1430914 Hom.: 5 Cov.: 0 AF XY: 0.0321 AC XY: 22830 AN XY: 712064

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

African (AFR) AF: 0.0159 AC: 525 AN: 32956

American (AMR) AF: 0.0280 AC: 1228 AN: 43846

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 796 AN: 25634

East Asian (EAS) AF: 0.00816 AC: 319 AN: 39114

South Asian (SAS) AF: 0.0223 AC: 1896 AN: 85120

European-Finnish (FIN) AF: 0.0451 AC: 2153 AN: 47758

Middle Eastern (MID) AF: 0.0164 AC: 92 AN: 5614

European-Non Finnish (NFE) AF: 0.0343 AC: 37469 AN: 1091698

Other (OTH) AF: 0.0294 AC: 1738 AN: 59174

⚠️ 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: 0.0321 AC: 4733 AN: 147584 Hom.: 83 Cov.: 0 AF XY: 0.0321 AC XY: 2300 AN XY: 71702

African (AFR) AF: 0.0185 AC: 738 AN: 39948

American (AMR) AF: 0.0342 AC: 510 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 112 AN: 3402

East Asian (EAS) AF: 0.00868 AC: 43 AN: 4956

South Asian (SAS) AF: 0.0206 AC: 95 AN: 4608

European-Finnish (FIN) AF: 0.0543 AC: 538 AN: 9900

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0388 AC: 2588 AN: 66630

Other (OTH) AF: 0.0308 AC: 63 AN: 2048

Alfa AF: 0.0163 Hom.: 197

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
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; COSMIC: COSV57154548; COSMIC: COSV57154548;