chr1-161222479-T-G

Variant names:

• chr1-161222479-T-G
• rs1666185995
• NM_001643.2:c.229A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001643.2(APOA2):​c.229A>C​(p.Lys77Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: APOA2 NM_001643.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.248

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.086987466).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA2	NM_001643.2	c.229A>C	p.Lys77Gln	missense_variant	Exon 4 of 4	ENST00000367990.7	NP_001634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA2	ENST00000367990.7	c.229A>C	p.Lys77Gln	missense_variant	Exon 4 of 4	1	NM_001643.2	ENSP00000356969.3
APOA2	ENST00000470459.6	c.201-26A>C		intron_variant	Intron 4 of 4	5		ENSP00000477031.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461884 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229A>C (p.K77Q) alteration is located in exon 4 (coding exon 3) of the APOA2 gene. This alteration results from a A to C substitution at nucleotide position 229, causing the lysine (K) at amino acid position 77 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Apolipoprotein A-II deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T;T;T;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.61	T;.;T;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.087	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.92	N;.;.;.;.
REVEL	Benign	0.014
Sift	Benign	0.49	T;.;.;.;.
Sift4G	Benign	0.40	T;D;D;T;T
Polyphen		0.058	B;.;.;.;.
Vest4		0.13
MutPred		0.38		Loss of methylation at K77 (P = 0.0075);.;.;.;Loss of methylation at K77 (P = 0.0075);
MVP		0.19
MPC		0.34
ClinPred		0.070	T
GERP RS		1.1
Varity_R		0.089
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1666185995; hg19: chr1-161192269;