Genetic Variant NM_001643.2:c.53-13_53-6dupTGTGTGTG (chr1-161223055-C-CCACACACA) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_001643.2(APOA2):c.53-13_53-6dupTGTGTGTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

APOA2
NM_001643.2 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Likely_benign. The variant received -1 ACMG points.

BS2

High AC in GnomAd4 at 94 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.53-13_53-6dupTGTGTGTG		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.53-13_53-6dupTGTGTGTG	splice_region intron	N/A	ENSP00000356969.3	P02652
APOA2	ENST00000463273.6	TSL:1	c.53-13_53-6dupTGTGTGTG	splice_region intron	N/A	ENSP00000476740.2	P02652
APOA2	ENST00000470459.6	TSL:5	c.53-13_53-6dupTGTGTGTG	splice_region intron	N/A	ENSP00000477031.1	V9GYS1

Frequencies

GnomAD3 genomes

AF:

0.000637

AC:

AN:

147522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000904

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00148

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000433

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000465

Gnomad OTH

AF:

0.00148

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000337

AC:

485

AN:

1440376

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

252

AN XY:

716634

show subpopulations

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

African (AFR)

AF:

0.000423

AC:

AN:

33080

American (AMR)

AF:

0.000682

AC:

AN:

44020

Ashkenazi Jewish (ASJ)

AF:

0.000194

AC:

AN:

25774

East Asian (EAS)

AF:

0.00

AC:

AN:

39170

South Asian (SAS)

AF:

0.000949

AC:

AN:

85362

European-Finnish (FIN)

AF:

0.0000208

AC:

AN:

48052

Middle Eastern (MID)

AF:

0.00373

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.000268

AC:

295

AN:

1099736

Other (OTH)

AF:

0.000638

AC:

AN:

59550

⚠️ 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: 0.314

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000637

AC:

AN:

147634

Hom.:

Cov.:

AF XY:

0.000669

AC XY:

AN XY:

71728

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

39956

American (AMR)

AF:

0.00148

AC:

AN:

14900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

4958

South Asian (SAS)

AF:

0.000434

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9922

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000465

AC:

AN:

66646

Other (OTH)

AF:

0.000977

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

197

Bravo

AF:

0.000892

ClinVar

Not reported in ClinVar

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

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