1-161222461-G-T

Variant names:

• chr1-161222461-G-T
• rs5088
• NM_001643.2:c.247C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001643.2(APOA2):​c.247C>A​(p.Leu83Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L83Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: APOA2 NM_001643.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.247C>A	p.Leu83Met	missense	Exon 4 of 4	NP_001634.1	P02652

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA2	ENST00000367990.7	TSL:1 MANE Select	c.247C>A	p.Leu83Met	missense	Exon 4 of 4	ENSP00000356969.3	P02652
	APOA2	ENST00000463273.6	TSL:1	c.247C>A	p.Leu83Met	missense	Exon 3 of 3	ENSP00000476740.2	P02652
	APOA2	ENST00000491350.1	TSL:1	c.*30C>A		3_prime_UTR	Exon 2 of 2	ENSP00000477353.1	Q76EI7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.077
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.24
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.84		Gain of methylation at K78 (P = 0.098)
MVP		0.15
MPC		0.90
ClinPred		0.26	T
GERP RS		1.9
Varity_R		0.10
gMVP		0.39
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 12

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

Other links and lift over

dbSNP: rs5088; hg19: chr1-161192251;