1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACACACACACACACACA

Variant names:

• chr1-161223055-C-CCACACA
• rs17244502
• NM_001643.2:c.53-11_53-6dupTGTGTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6_Very_Strong BS2_Supporting

The NM_001643.2(APOA2):​c.53-11_53-6dupTGTGTG 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 0.0029 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00064 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts 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 -9 ACMG points.

• BP6: Variant 1-161223055-C-CCACACA is Benign according to our data. Variant chr1-161223055-C-CCACACA is described in ClinVar as Benign. ClinVar VariationId is 1337962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 423 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.53-11_53-6dupTGTGTG		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.53-11_53-6dupTGTGTG		splice_region intron	N/A	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.53-11_53-6dupTGTGTG		splice_region intron	N/A	ENSP00000476740.2	P02652
	APOA2	ENST00000470459.6	TSL:5	c.53-11_53-6dupTGTGTG		splice_region intron	N/A	ENSP00000477031.1	V9GYS1

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 423 AN: 147514 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00899

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000660

Gnomad OTH AF: 0.00197

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000635 AC: 915 AN: 1439968 Hom.: 1 Cov.: 0 AF XY: 0.000662 AC XY: 474 AN XY: 716404

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

African (AFR) AF: 0.00654 AC: 215 AN: 32898

American (AMR) AF: 0.000795 AC: 35 AN: 44022

Ashkenazi Jewish (ASJ) AF: 0.0000776 AC: 2 AN: 25778

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39172

South Asian (SAS) AF: 0.00118 AC: 101 AN: 85360

European-Finnish (FIN) AF: 0.0000832 AC: 4 AN: 48050

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5640

European-Non Finnish (NFE) AF: 0.000449 AC: 494 AN: 1099510

Other (OTH) AF: 0.000907 AC: 54 AN: 59538

⚠️ 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: 0.00287 AC: 423 AN: 147626 Hom.: 1 Cov.: 0 AF XY: 0.00276 AC XY: 198 AN XY: 71722

African (AFR) AF: 0.00896 AC: 358 AN: 39948

American (AMR) AF: 0.00107 AC: 16 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 4958

South Asian (SAS) AF: 0.000217 AC: 1 AN: 4606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9922

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

European-Non Finnish (NFE) AF: 0.000660 AC: 44 AN: 66646

Other (OTH) AF: 0.00195 AC: 4 AN: 2048

Alfa AF: 0.00 Hom.: 197

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17244502; hg19: chr1-161192845;