22-36227583-T-G

Variant names:

• chr22-36227583-T-G
• rs772205206
• NM_030882.4:c.835A>C

Variant summary

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

The NM_030882.4(APOL2):​c.835A>C​(p.Thr279Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T279I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: APOL2 NM_030882.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.35

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOL2	NM_030882.4	c.835A>C	p.Thr279Pro	missense_variant	Exon 5 of 5	ENST00000358502.10	NP_112092.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOL2	ENST00000358502.10	c.835A>C	p.Thr279Pro	missense_variant	Exon 5 of 5	1	NM_030882.4	ENSP00000351292.5
APOL2	ENST00000249066.10	c.835A>C	p.Thr279Pro	missense_variant	Exon 6 of 6	1		ENSP00000249066.6
APOL2	ENST00000451256.6	c.1171A>C	p.Thr391Pro	missense_variant	Exon 6 of 6	2		ENSP00000403153.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249822 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135420

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.835A>C (p.T279P) alteration is located in exon 6 (coding exon 3) of the APOL2 gene. This alteration results from a A to C substitution at nucleotide position 835, causing the threonine (T) at amino acid position 279 to be replaced by a proline (P). 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	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.088
DANN	Benign	0.52
DEOGEN2	Benign	0.065	.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.32	.;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.13
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.10	T;T;T
Vest4		0.26
MutPred		0.83		Loss of catalytic residue at T279 (P = 0.0489);Loss of catalytic residue at T279 (P = 0.0489);.;
MVP		0.067
MPC		0.088
ClinPred		0.063	T
GERP RS		-7.3
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs772205206; hg19: chr22-36623629;