Genetic Variant APOA2:c.53-7_53-6dupTG (chr1-161223055-C-CCA) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP6_Very_StrongBS1BS2_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

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.116

Publications

4 publications found

Variant links:

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

APOA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	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.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.0321

AC XY:

22830

AN XY:

712064

show subpopulations

⚠️ 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:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

2824

5648

8472

11296

14120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1440

2880

4320

5760

7200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0321

AC:

4733

AN:

147584

Hom.:

Cov.:

AF XY:

0.0321

AC XY:

2300

AN XY:

71702

show subpopulations

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:

AN:

4956

South Asian (SAS)

AF:

0.0206

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.0543

AC:

538

AN:

9900

Middle Eastern (MID)

AF:

0.0205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0388

AC:

2588

AN:

66630

Other (OTH)

AF:

0.0308

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

206

411

617

822

1028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0163

Hom.:

197

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.12

Mutation Taster

=100/0

polymorphism

(source)

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.

Publications

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1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACACACACACACA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over