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. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

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

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]

ACMG classification

Verdict is Benign. Variant got -8 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 id is 1337962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA2	NM_001643.2	c.53-11_53-6dupTGTGTG		splice_region_variant, intron_variant	Intron 2 of 3	ENST00000367990.7	NP_001634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA2	ENST00000367990.7	c.53-11_53-6dupTGTGTG		splice_region_variant, intron_variant	Intron 2 of 3	1	NM_001643.2	ENSP00000356969.3
APOA2	ENST00000470459.6	c.53-11_53-6dupTGTGTG		splice_region_variant, intron_variant	Intron 2 of 4	5		ENSP00000477031.1

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

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.000795

Gnomad4 ASJ exome AF: 0.0000776

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.00118

Gnomad4 FIN exome AF: 0.0000832

Gnomad4 NFE exome AF: 0.000449

Gnomad4 OTH exome AF: 0.000907

GnomAD4 genome AF: 0.00287 AC: 423 AN: 147626 Hom.: 1 Cov.: 0 AF XY: 0.00276 AC XY: 198 AN XY: 71722

Gnomad4 AFR AF: 0.00896

Gnomad4 AMR AF: 0.00107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000217

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000660

Gnomad4 OTH AF: 0.00195

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 12, 2023

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.53-11_53-6dupTGTGTG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This specific duplication was absent in 195520 control chromosomes, however, this intronic region has a long expanse of [TG] repeats. Several other [TG] duplications and deletions have been found in this region, some with allele frequencies as high as 0.2874 (c.53-11_53-6delTGTGTG, gnomAD). To our knowledge, no occurrence of c.53-11_53-6dupTGTGTG in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as benign. Based on the evidence outlined above, the variant was classified as benign. -

Jun 07, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs17244502; hg19: chr1-161192845;