Genetic Variant PPIC:p.Leu124Val (chr5-123025924-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000943.5(PPIC):c.370C>G(p.Leu124Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L124M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PPIC
NM_000943.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.74

Publications

0 publications found

Variant links:

Genes affected

PPIC (HGNC:9256): (peptidylprolyl isomerase C) The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase)) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. Similar to other PPIases, this protein can bind immunosuppressant cyclosporin A. [provided by RefSeq, Jul 2008]

PPIC links:

SNX24 (HGNC:21533): (sorting nexin 24) Predicted to enable phosphatidylinositol phosphate binding activity. Predicted to be involved in protein transport. Predicted to be located in cytoplasmic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

SNX24 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000943.5. 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
	PPIC	NM_000943.5	MANE Select	c.370C>G	p.Leu124Val	missense	Exon 4 of 5	NP_000934.1	P45877

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPIC	ENST00000306442.5	TSL:1 MANE Select	c.370C>G	p.Leu124Val	missense	Exon 4 of 5	ENSP00000303057.4	P45877
PPIC	ENST00000910736.1		c.511C>G	p.Leu171Val	missense	Exon 5 of 6	ENSP00000580795.1
PPIC	ENST00000910735.1		c.370C>G	p.Leu124Val	missense	Exon 4 of 6	ENSP00000580794.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

247158

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33264

American (AMR)

AF:

0.00

AC:

AN:

43724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39656

South Asian (SAS)

AF:

0.00

AC:

AN:

84938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110826

Other (OTH)

AF:

0.00

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.6

PhyloP100

4.7

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.39

Sift

Benign

0.030

Sift4G

Benign

0.065

Polyphen

1.0

Vest4

0.49

MutPred

0.66

Loss of stability (P = 0.0354)

MVP

0.61

MPC

0.62

ClinPred

0.93

GERP RS

5.2

Varity_R

0.84

gMVP

0.51

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over