rs6413453

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-161222526-G-A
• chr1-161222526-G-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.

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.186-4C>T		splice_region intron	N/A	NP_001634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA2	ENST00000367990.7	TSL:1 MANE Select	c.186-4C>T		splice_region intron	N/A	ENSP00000356969.3
	APOA2	ENST00000463273.6	TSL:1	c.186-4C>T		splice_region intron	N/A	ENSP00000476740.2
	APOA2	ENST00000470459.6	TSL:5	c.186-4C>T		splice_region intron	N/A	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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	APOA2-related disorder (1)
-	-	1	APOLIPOPROTEIN A-II DEFICIENCY (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;