22-21686963-A-G

Position:

• chr22-21686963-A-G

Variant summary

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

The NM_014337.4(PPIL2):​c.862A>G​(p.Lys288Glu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPIL2 NM_014337.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39

Genes affected

PPIL2 (HGNC:9261): (peptidylprolyl isomerase like 2) This gene is a member of the cyclophilin family of peptidylprolyl isomerases. The cyclophilins are a highly conserved ubiquitous family, members of which play an important role in protein folding, immunosuppression by cyclosporin A, and infection of HIV-1 virions. This protein interacts with the proteinase inhibitor eglin c and is localized in the nucleus. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

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=0.26095366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPIL2	NM_014337.4	c.862A>G	p.Lys288Glu	missense_variant	12/20	ENST00000398831.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPIL2	ENST00000398831.8	c.862A>G	p.Lys288Glu	missense_variant	12/20	1	NM_014337.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Oct 06, 2021

The c.862A>G (p.K288E) alteration is located in exon 12 (coding exon 12) of the PPIL2 gene. This alteration results from a A to G substitution at nucleotide position 862, causing the lysine (K) at amino acid position 288 to be replaced by a glutamic acid (E). 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	0.18
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T;T;.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	.;.;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.89	N;N;.;N
REVEL	Benign	0.074
Sift	Benign	0.27	T;T;.;T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.49
MutPred		0.41		Loss of ubiquitination at K288 (P = 0.0127);Loss of ubiquitination at K288 (P = 0.0127);Loss of ubiquitination at K288 (P = 0.0127);Loss of ubiquitination at K288 (P = 0.0127);
MVP		0.41
ClinPred		0.51	D
GERP RS		-0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-22041252;