9-125153700-G-C

Variant names:

• chr9-125153700-G-C
• NM_002721.5:c.502C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_002721.5(PPP6C):​c.502C>G​(p.Pro168Ala) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP6C NM_002721.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55
• Publications: 0 publications found

Genes affected

PPP6C (HGNC:9323): (protein phosphatase 6 catalytic subunit) This gene encodes the catalytic subunit of protein phosphatase, a component of a signaling pathway regulating cell cycle progression. Splice variants encoding different protein isoforms exist. The pseudogene of this gene is located on chromosome X. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.5825 (below the threshold of 3.09). Trascript score misZ: 3.0646 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002721.5. 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
	PPP6C	NM_002721.5	MANE Select	c.502C>G	p.Pro168Ala	missense	Exon 6 of 7	NP_002712.1	A0A024R861
	PPP6C	NM_001123355.2		c.613C>G	p.Pro205Ala	missense	Exon 7 of 8	NP_001116827.1	O00743-3
	PPP6C	NM_001123369.2		c.436C>G	p.Pro146Ala	missense	Exon 5 of 6	NP_001116841.1	O00743-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP6C	ENST00000373547.9	TSL:1 MANE Select	c.502C>G	p.Pro168Ala	missense	Exon 6 of 7	ENSP00000362648.4	O00743-1
	PPP6C	ENST00000451402.5	TSL:2	c.613C>G	p.Pro205Ala	missense	Exon 7 of 8	ENSP00000392147.1	O00743-3
	PPP6C	ENST00000889868.1		c.547C>G	p.Pro183Ala	missense	Exon 6 of 7	ENSP00000559927.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.89		Loss of ubiquitination at K171 (P = 0.0777)
MVP		0.69
MPC		1.9
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.88
Mutation Taster		=29/71	disease causing

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

Other links and lift over

hg19: chr9-127915979; COSMIC: COSV101001244; COSMIC: COSV101001244;