chr1-161223055-C-CCACA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6 BS2_Supporting

The NM_001643.2(APOA2):​c.53-9_53-6dupTGTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0086 (10 hom., cov: 0)
  • Exomes 𝑓: 0.0065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• 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 -2 ACMG points.

• BP6: Variant 1-161223055-C-CCACA is Benign according to our data. Variant chr1-161223055-C-CCACA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 293293.
• BS2: High AC in GnomAd4 at 1265 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_53-6dupTGTG		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_53-6dupTGTG		splice_region intron	N/A	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.53-9_53-6dupTGTG		splice_region intron	N/A	ENSP00000476740.2	P02652
	APOA2	ENST00000470459.6	TSL:5	c.53-9_53-6dupTGTG		splice_region intron	N/A	ENSP00000477031.1	V9GYS1

Frequencies

GnomAD3 genomes AF: 0.00858 AC: 1266 AN: 147508 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.00979

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00672

Gnomad ASJ AF: 0.0168

Gnomad EAS AF: 0.000604

Gnomad SAS AF: 0.00997

Gnomad FIN AF: 0.00807

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00861

Gnomad OTH AF: 0.00592

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00651 AC: 9344 AN: 1436274 Hom.: 0 Cov.: 0 AF XY: 0.00676 AC XY: 4830 AN XY: 714690

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

African (AFR) AF: 0.00659 AC: 217 AN: 32944

American (AMR) AF: 0.00434 AC: 191 AN: 43980

Ashkenazi Jewish (ASJ) AF: 0.00992 AC: 255 AN: 25706

East Asian (EAS) AF: 0.000255 AC: 10 AN: 39168

South Asian (SAS) AF: 0.00935 AC: 797 AN: 85200

European-Finnish (FIN) AF: 0.00581 AC: 279 AN: 47994

Middle Eastern (MID) AF: 0.00998 AC: 56 AN: 5614

European-Non Finnish (NFE) AF: 0.00651 AC: 7142 AN: 1096244

Other (OTH) AF: 0.00668 AC: 397 AN: 59424

⚠️ 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: 0.00857 AC: 1265 AN: 147620 Hom.: 10 Cov.: 0 AF XY: 0.00892 AC XY: 640 AN XY: 71724

African (AFR) AF: 0.00979 AC: 391 AN: 39950

American (AMR) AF: 0.00664 AC: 99 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 57 AN: 3402

East Asian (EAS) AF: 0.000605 AC: 3 AN: 4958

South Asian (SAS) AF: 0.00998 AC: 46 AN: 4608

European-Finnish (FIN) AF: 0.00807 AC: 80 AN: 9918

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

European-Non Finnish (NFE) AF: 0.00861 AC: 574 AN: 66640

Other (OTH) AF: 0.00586 AC: 12 AN: 2048

Alfa AF: 0.00246 Hom.: 197

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	APOLIPOPROTEIN A-II DEFICIENCY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=98/2	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;