chr1-161222526-G-A

Variant names:

• chr1-161222526-G-A
• rs6413453
• NM_001643.2:c.186-4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001643.2(APOA2):​c.186-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,611,414 control chromosomes in the GnomAD database, including 10,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (702 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9987 hom.)
• Consequence: APOA2 NM_001643.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002164
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.12
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-161222526-G-A is Benign according to our data. Variant chr1-161222526-G-A is described in ClinVar as Benign. ClinVar VariationId is 293292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA2	NM_001643.2	c.186-4C>T		splice_region_variant, intron_variant	Intron 3 of 3	ENST00000367990.7	NP_001634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA2	ENST00000367990.7	c.186-4C>T		splice_region_variant, intron_variant	Intron 3 of 3	1	NM_001643.2	ENSP00000356969.3
APOA2	ENST00000470459.6	c.186-4C>T		splice_region_variant, intron_variant	Intron 3 of 4	5		ENSP00000477031.1

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 13230 AN: 152150 Hom.: 697 Cov.: 31

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0925

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0880

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0832

GnomAD2 exomes AF: 0.111 AC: 27874 AN: 251262 AF XY: 0.113

Gnomad AFR exome AF: 0.0276

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.0925

Gnomad NFE exome AF: 0.114

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.113 AC: 165438 AN: 1459146 Hom.: 9987 Cov.: 29 AF XY: 0.114 AC XY: 82432 AN XY: 726156

African (AFR) AF: 0.0284 AC: 948 AN: 33432

American (AMR) AF: 0.110 AC: 4920 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0480 AC: 1254 AN: 26114

East Asian (EAS) AF: 0.201 AC: 7965 AN: 39684

South Asian (SAS) AF: 0.141 AC: 12165 AN: 86202

European-Finnish (FIN) AF: 0.0957 AC: 5110 AN: 53406

Middle Eastern (MID) AF: 0.0681 AC: 391 AN: 5744

European-Non Finnish (NFE) AF: 0.114 AC: 126026 AN: 1109550

Other (OTH) AF: 0.110 AC: 6659 AN: 60302

GnomAD4 genome AF: 0.0870 AC: 13249 AN: 152268 Hom.: 702 Cov.: 31 AF XY: 0.0875 AC XY: 6514 AN XY: 74436

African (AFR) AF: 0.0309 AC: 1285 AN: 41570

American (AMR) AF: 0.0935 AC: 1431 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 165 AN: 3470

East Asian (EAS) AF: 0.165 AC: 851 AN: 5170

South Asian (SAS) AF: 0.148 AC: 711 AN: 4816

European-Finnish (FIN) AF: 0.0880 AC: 933 AN: 10608

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7572 AN: 68014

Other (OTH) AF: 0.0828 AC: 175 AN: 2114

Alfa AF: 0.102 Hom.: 798

Bravo AF: 0.0851

Asia WGS AF: 0.159 AC: 552 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

APOA2-related disorder Benign:1

Mar 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apolipoprotein A-II deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.8
DANN	Benign	0.66
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs6413453; hg19: chr1-161192316; COSMIC: COSV57154137; COSMIC: COSV57154137;