12-110722665-T-A

Position:

• chr12-110722665-T-A

Variant summary

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

The NM_002710.4(PPP1CC):​c.554A>T​(p.Gln185Leu) 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: PPP1CC NM_002710.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

Genes affected

PPP1CC (HGNC:9283): (protein phosphatase 1 catalytic subunit gamma) The protein encoded by this gene belongs to the protein phosphatase family, PP1 subfamily. PP1 is an ubiquitous serine/threonine phosphatase that regulates many cellular processes, including cell division. It is expressed in mammalian cells as three closely related isoforms, alpha, beta/delta and gamma, which have distinct localization patterns. This gene encodes the gamma isozyme. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

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, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1CC	NM_002710.4	c.554A>T	p.Gln185Leu	missense_variant	5/7	ENST00000335007.10	NP_002701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1CC	ENST00000335007.10	c.554A>T	p.Gln185Leu	missense_variant	5/7	1	NM_002710.4	ENSP00000335084	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.554A>T (p.Q185L) alteration is located in exon 5 (coding exon 5) of the PPP1CC gene. This alteration results from a A to T substitution at nucleotide position 554, causing the glutamine (Q) at amino acid position 185 to be replaced by a leucine (L). 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	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.;T;D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.2	D;D;.;D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;.;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		0.84	P;.;.;.;.;.
Vest4		0.74
MutPred		0.50		Gain of catalytic residue at E184 (P = 0.0343);Gain of catalytic residue at E184 (P = 0.0343);.;.;Gain of catalytic residue at E184 (P = 0.0343);Gain of catalytic residue at E184 (P = 0.0343);
MVP		0.35
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.93
gMVP		0.97

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-111160470;