9-125189704-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002721.5(PPP6C):c.15C>A(p.Asp5Glu) variant causes a missense 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP6C NM_002721.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2741707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP6C	NM_002721.5	c.15C>A	p.Asp5Glu	missense_variant	1/7	ENST00000373547.9
PPP6C	NM_001123355.2	c.15C>A	p.Asp5Glu	missense_variant	1/8
PPP6C	NM_001123369.2	c.15C>A	p.Asp5Glu	missense_variant	1/6
PPP6C	XM_047423566.1	c.15C>A	p.Asp5Glu	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP6C	ENST00000373547.9	c.15C>A	p.Asp5Glu	missense_variant	1/7	1	NM_002721.5	P1
PPP6C	ENST00000451402.5	c.15C>A	p.Asp5Glu	missense_variant	1/8	2
PPP6C	ENST00000415905.5	c.15C>A	p.Asp5Glu	missense_variant	1/6	2
PPP6C	ENST00000456642.1	c.-115C>A		5_prime_UTR_variant	1/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.15C>A (p.D5E) alteration is located in exon 1 (coding exon 1) of the PPP6C gene. This alteration results from a C to A substitution at nucleotide position 15, causing the aspartic acid (D) at amino acid position 5 to be replaced by a glutamic acid (E). 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	Benign	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.080
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0060	B;B;B
Vest4		0.64
MutPred		0.49		Gain of ubiquitination at K8 (P = 0.1025);Gain of ubiquitination at K8 (P = 0.1025);Gain of ubiquitination at K8 (P = 0.1025);
MVP		0.60
MPC		0.84
ClinPred		0.31	T
GERP RS		2.4
Varity_R		0.080
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-127951983;