8-22527394-G-T

Variant names:

• chr8-22527394-G-T
• rs1839586041
• NM_005605.5:c.946G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005605.5(PPP3CC):​c.946G>T​(p.Ala316Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP3CC NM_005605.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

ENSG00000251034 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CC	NM_005605.5	c.946G>T	p.Ala316Ser	missense_variant, splice_region_variant	Exon 9 of 14	ENST00000240139.10	NP_005596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CC	ENST00000240139.10	c.946G>T	p.Ala316Ser	missense_variant, splice_region_variant	Exon 9 of 14	1	NM_005605.5	ENSP00000240139.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.946G>T (p.A316S) alteration is located in exon 9 (coding exon 9) of the PPP3CC gene. This alteration results from a G to T substitution at nucleotide position 946, causing the alanine (A) at amino acid position 316 to be replaced by a serine (S). 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.2	M;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.093	T;T;T
Polyphen		0.95	P;D;.
Vest4		0.76
MutPred		0.69		Gain of ubiquitination at K319 (P = 0.1096);Gain of ubiquitination at K319 (P = 0.1096);Gain of ubiquitination at K319 (P = 0.1096);
MVP		0.69
MPC		0.58
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1839586041; hg19: chr8-22384907;