rs778751126

Variant names:

• chr1-161222460-A-G
• rs778751126
• NM_001643.2:c.248T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-161222460-A-G
• chr1-161222460-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001643.2(APOA2):​c.248T>C​(p.Leu83Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 2.68

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA2	NM_001643.2	c.248T>C	p.Leu83Pro	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.248T>C	p.Leu83Pro	missense_variant	Exon 4 of 4	1	NM_001643.2	ENSP00000356969.3
APOA2	ENST00000470459.6	c.201-7T>C		splice_region_variant, intron_variant	Intron 4 of 4	5		ENSP00000477031.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Benign	0.70
DEOGEN2	Pathogenic	0.82	D;T;T;T;.
Eigen	Benign	-0.047
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.65	T;.;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.1	D;.;.;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D;.;.;.;.
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.87
MutPred		0.89		Gain of loop (P = 0.0079);.;.;.;Gain of loop (P = 0.0079);
MVP		0.51
MPC		1.2
ClinPred		0.86	D
GERP RS		3.8
Varity_R		0.78
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs778751126; hg19: chr1-161192250;