22-21695494-C-A

Variant names:

• chr22-21695494-C-A
• rs12484060
• ENST00000626352.2:c.1563C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_148176.3(PPIL2):​c.1563C>A​(p.Ser521Arg) variant causes a missense, splice region 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. 14/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S521S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPIL2 NM_148176.3 missense, splice_region
• Scores: Splicing: ADA: 0.0004956
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.739
• Publications: 30 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056188524).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_148176.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPIL2	NM_014337.4	MANE Select	c.*4C>A		3_prime_UTR	Exon 20 of 20	NP_055152.1	Q13356-1
	PPIL2	NM_148176.3		c.1563C>A	p.Ser521Arg	missense splice_region	Exon 20 of 21	NP_680481.1	Q13356-2
	PPIL2	NM_001317996.2		c.*4C>A		splice_region	Exon 20 of 21	NP_001304925.1	Q13356-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPIL2	ENST00000626352.2	TSL:1	c.1563C>A	p.Ser521Arg	missense splice_region	Exon 20 of 21	ENSP00000486725.1	Q13356-2
	PPIL2	ENST00000335025.12	TSL:1	c.*4C>A		splice_region	Exon 20 of 21	ENSP00000334553.7	Q13356-1
	PPIL2	ENST00000406385.1	TSL:1	c.*4C>A		splice_region	Exon 20 of 21	ENSP00000384299.1	Q13356-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1437880 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 712838

African (AFR) AF: 0.00 AC: 0 AN: 33100

American (AMR) AF: 0.00 AC: 0 AN: 41058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 38876

South Asian (SAS) AF: 0.00 AC: 0 AN: 82842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099568

Other (OTH) AF: 0.00 AC: 0 AN: 59532

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 10117

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Uncertain	0.98
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.74
PrimateAI	Benign	0.36	T
Sift4G	Uncertain	0.029	D
Polyphen		0.0	B
Vest4		0.22
MutPred		0.13		Loss of phosphorylation at S521 (P = 0.014)
MVP		0.32
ClinPred		0.29	T
GERP RS		0.93
gMVP		0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.086
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

Other links and lift over

dbSNP: rs12484060; hg19: chr22-22049783;