Genetic Variant NM_005605.5:c.127A>G (chr8-22475031-A-G) – 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_005605.5(PPP3CC):c.127A>G(p.Lys43Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,902 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K43Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PPP3CC
NM_005605.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.00

Publications

0 publications found

Variant links:

Genes affected

PPP3CC (HGNC:9316): (protein phosphatase 3 catalytic subunit gamma) Calcineurin is a calcium-dependent, calmodulin-stimulated protein phosphatase involved in the downstream regulation of dopaminergic signal transduction. Calcineurin is composed of a regulatory subunit and a catalytic subunit. The protein encoded by this gene represents one of the regulatory subunits that has been found for calcineurin. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

PPP3CC Gene-Disease associations (from GenCC):

schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

PPP3CC 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_005605.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP3CC	NM_005605.5	MANE Select	c.127A>G	p.Lys43Glu	missense	Exon 2 of 14	NP_005596.2
PPP3CC	NM_001243974.2		c.127A>G	p.Lys43Glu	missense	Exon 2 of 15	NP_001230903.1	P48454-3
PPP3CC	NM_001243975.2		c.127A>G	p.Lys43Glu	missense	Exon 2 of 13	NP_001230904.1	P48454-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP3CC	ENST00000240139.10	TSL:1 MANE Select	c.127A>G	p.Lys43Glu	missense	Exon 2 of 14	ENSP00000240139.5	P48454-1
PPP3CC	ENST00000289963.12	TSL:1	c.127A>G	p.Lys43Glu	missense	Exon 2 of 13	ENSP00000289963.8	P48454-2
PPP3CC	ENST00000968566.1		c.127A>G	p.Lys43Glu	missense	Exon 2 of 14	ENSP00000638625.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460902

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111360

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.59

MetaSVM

Uncertain

0.068

MutationAssessor

Pathogenic

3.7

PhyloP100

6.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.37

Sift

Uncertain

0.0010

Sift4G

Benign

0.11

Polyphen

0.67

Vest4

0.66

MutPred

0.52

Gain of ubiquitination at K38 (P = 0.0435)

MVP

0.86

MPC

0.86

ClinPred

0.99

GERP RS

5.8

Varity_R

0.58

gMVP

0.83

Mutation Taster

=66/34

polymorphism

(source)

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

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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