19-46375716-G-C

Variant names:

• chr19-46375716-G-C
• rs751265952
• NM_006247.4:c.476G>C

Variant summary

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

The NM_006247.4(PPP5C):​c.476G>C​(p.Arg159Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,020 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. R159H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PPP5C NM_006247.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• Publications: 0 publications found

Genes affected

PPP5C (HGNC:9322): (protein phosphatase 5 catalytic subunit) This gene encodes a serine/threonine phosphatase which is a member of the protein phosphatase catalytic subunit family. Proteins in this family participate in pathways regulated by reversible phosphorylation at serine and threonine residues; many of these pathways are involved in the regulation of cell growth and differentiation. The product of this gene has been shown to participate in signaling pathways in response to hormones or cellular stress, and elevated levels of this protein may be associated with breast cancer development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2011]

PPP5C-AS1 (HGNC:58175):

ACMG classification

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_006247.4. 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
	PPP5C	NM_006247.4	MANE Select	c.476G>C	p.Arg159Pro	missense	Exon 3 of 13	NP_006238.1	P53041
	PPP5C	NM_001204284.2		c.476G>C	p.Arg159Pro	missense	Exon 3 of 12	NP_001191213.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP5C	ENST00000012443.9	TSL:1 MANE Select	c.476G>C	p.Arg159Pro	missense	Exon 3 of 13	ENSP00000012443.4	P53041
	PPP5C	ENST00000478046.5	TSL:1	n.470G>C		non_coding_transcript_exon	Exon 3 of 14	ENSP00000434329.1	H0YDU8
	PPP5C	ENST00000923870.1		c.509G>C	p.Arg170Pro	missense	Exon 3 of 13	ENSP00000593929.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457020 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724420

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 44038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 85474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109648

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Benign	0.32
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.12	N
PhyloP100		5.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.26
Sift	Benign	0.47	T
Sift4G	Benign	0.30	T
Polyphen		0.019	B
Vest4		0.57
MutPred		0.63		Gain of ubiquitination at K158 (P = 0.0851)
MVP		0.72
MPC		1.0
ClinPred		0.81	D
GERP RS		2.2
Varity_R		0.62
gMVP		0.75
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs751265952; hg19: chr19-46878973;