11-67399650-T-C

Variant names:

• chr11-67399650-T-C
• NM_002708.4:c.434A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002708.4(PPP1CA):​c.434A>G​(p.Asn145Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP1CA NM_002708.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

Genes affected

PPP1CA (HGNC:9281): (protein phosphatase 1 catalytic subunit alpha) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). This broadly expressed gene encodes the alpha subunit of the PP1 complex that associates with over 200 regulatory proteins to form holoenzymes which dephosphorylate their biological targets with high specificity. PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Increased PP1 activity has been observed in the end stage of heart failure. Studies suggest that PP1 is an important regulator of cardiac function and that PP1 deregulation is implicated in diabetes and multiple types of cancer. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CA	NM_002708.4	c.434A>G	p.Asn145Ser	missense_variant	Exon 4 of 7	ENST00000376745.9	NP_002699.1
PPP1CA	NM_001008709.2	c.467A>G	p.Asn156Ser	missense_variant	Exon 4 of 7		NP_001008709.1
PPP1CA	NM_206873.2	c.302A>G	p.Asn101Ser	missense_variant	Exon 3 of 6		NP_996756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CA	ENST00000376745.9	c.434A>G	p.Asn145Ser	missense_variant	Exon 4 of 7	1	NM_002708.4	ENSP00000365936.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.467A>G (p.N156S) alteration is located in exon 4 (coding exon 4) of the PPP1CA gene. This alteration results from a A to G substitution at nucleotide position 467, causing the asparagine (N) at amino acid position 156 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	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.0024
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.20	.;N;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.81	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.73
MVP		0.28
MPC		1.2
ClinPred		0.87	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr11-67167121;