Genetic Variant APOA2:c.53-9_53-6dupTGTG (chr1-161223055-C-CCACA) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6BS2_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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

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

new If you want to explore the variant's impact on the transcript NM_001643.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	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.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00676

AC XY:

4830

AN XY:

714690

show subpopulations

⚠️ 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:

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:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.299

Heterozygous variant carriers

657

1315

1972

2630

3287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

260

520

780

1040

1300

<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:

0.00857

AC:

1265

AN:

147620

Hom.:

Cov.:

AF XY:

0.00892

AC XY:

640

AN XY:

71724

show subpopulations

African (AFR)

AF:

0.00979

AC:

391

AN:

39950

American (AMR)

AF:

0.00664

AC:

AN:

14902

Ashkenazi Jewish (ASJ)

AF:

0.0168

AC:

AN:

3402

East Asian (EAS)

AF:

0.000605

AC:

AN:

4958

South Asian (SAS)

AF:

0.00998

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.00807

AC:

AN:

9918

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00861

AC:

574

AN:

66640

Other (OTH)

AF:

0.00586

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00246

Hom.:

197

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

APOLIPOPROTEIN A-II DEFICIENCY (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.12

Mutation Taster

=98/2

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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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