1-161223055-CCACACACACACACACACACACACA-CCACACACACACACACACACACACACA

Variant summary

Our verdict is Benign. Variant got -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:5

Conservation

PhyloP100: 0.116
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 83 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APOA2NM_001643.2 linkc.53-7_53-6dupTG splice_region_variant, intron_variant Intron 2 of 3 ENST00000367990.7 NP_001634.1 P02652

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOA2ENST00000367990.7 linkc.53-7_53-6dupTG splice_region_variant, intron_variant Intron 2 of 3 1 NM_001643.2 ENSP00000356969.3 P02652
APOA2ENST00000470459.6 linkc.53-7_53-6dupTG splice_region_variant, intron_variant Intron 2 of 4 5 ENSP00000477031.1 V9GYS1

Frequencies

GnomAD3 genomes
AF:
0.0321
AC:
4735
AN:
147472
Hom.:
83
Cov.:
0
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.:
5
Cov.:
0
AF XY:
0.0321
AC XY:
22830
AN XY:
712064
show subpopulations
Gnomad4 AFR exome
AF:
0.0159
Gnomad4 AMR exome
AF:
0.0280
Gnomad4 ASJ exome
AF:
0.0311
Gnomad4 EAS exome
AF:
0.00816
Gnomad4 SAS exome
AF:
0.0223
Gnomad4 FIN exome
AF:
0.0451
Gnomad4 NFE exome
AF:
0.0343
Gnomad4 OTH exome
AF:
0.0294
GnomAD4 genome
AF:
0.0321
AC:
4733
AN:
147584
Hom.:
83
Cov.:
0
AF XY:
0.0321
AC XY:
2300
AN XY:
71702
show subpopulations
Gnomad4 AFR
AF:
0.0185
Gnomad4 AMR
AF:
0.0342
Gnomad4 ASJ
AF:
0.0329
Gnomad4 EAS
AF:
0.00868
Gnomad4 SAS
AF:
0.0206
Gnomad4 FIN
AF:
0.0543
Gnomad4 NFE
AF:
0.0388
Gnomad4 OTH
AF:
0.0308

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 23, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Benign:2
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 06, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: APOA2 c.53-7_53-6dupTG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.036 in 28768 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 1823-folds over the estimated maximal expected allele frequency for a pathogenic variant in APOA2 causing Early Onset Coronary Artery Disease phenotype (2e-05), strongly suggesting that the variant is benign. Co-occurrences with other pathogenic variant(s) have been reported (LDLR c.1567G>A, p.Val523Met). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs17244502; hg19: chr1-161192845; API