22-36227672-A-G

Position:

• chr22-36227672-A-G

Variant summary

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

The ENST00000358502.10(APOL2):​c.746T>C​(p.Ile249Thr) 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 benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APOL2 ENST00000358502.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.549

Genes affected

APOL2 (HGNC:619): (apolipoprotein L2) This gene is a member of the apolipoprotein L gene family. The encoded protein is found in the cytoplasm, where it may affect the movement of lipids or allow the binding of lipids to organelles. Two transcript variants encoding the same protein have been found for this gene. [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=0.16338328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOL2	NM_030882.4	c.746T>C	p.Ile249Thr	missense_variant	5/5	ENST00000358502.10	NP_112092.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOL2	ENST00000358502.10	c.746T>C	p.Ile249Thr	missense_variant	5/5	1	NM_030882.4	ENSP00000351292	P2
APOL2	ENST00000249066.10	c.746T>C	p.Ile249Thr	missense_variant	6/6	1		ENSP00000249066	P2
APOL2	ENST00000451256.6	c.1082T>C	p.Ile361Thr	missense_variant	6/6	2		ENSP00000403153	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2024

The c.746T>C (p.I249T) alteration is located in exon 6 (coding exon 3) of the APOL2 gene. This alteration results from a T to C substitution at nucleotide position 746, causing the isoleucine (I) at amino acid position 249 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.69
DANN	Benign	0.73
DEOGEN2	Benign	0.013	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.42	.;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.098
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.38	T;T;T
Vest4		0.026
MutPred		0.81		Loss of stability (P = 0.0672);Loss of stability (P = 0.0672);.;
MVP		0.055
MPC		0.092
ClinPred		0.24	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-36623718;