rs1367068828

Variant names:

• chr11-67399053-C-A
• rs1367068828
• NM_002708.4:c.634G>T

Variant summary

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

The NM_002708.4(PPP1CA):​c.634G>T​(p.Asp212Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PPP1CA NM_002708.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CA	NM_002708.4	c.634G>T	p.Asp212Tyr	missense_variant	Exon 5 of 7	ENST00000376745.9	NP_002699.1
PPP1CA	NM_001008709.2	c.667G>T	p.Asp223Tyr	missense_variant	Exon 5 of 7		NP_001008709.1
PPP1CA	NM_206873.2	c.502G>T	p.Asp168Tyr	missense_variant	Exon 4 of 6		NP_996756.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CA	ENST00000376745.9	c.634G>T	p.Asp212Tyr	missense_variant	Exon 5 of 7	1	NM_002708.4	ENSP00000365936.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.667G>T (p.D223Y) alteration is located in exon 5 (coding exon 5) of the PPP1CA gene. This alteration results from a G to T substitution at nucleotide position 667, causing the aspartic acid (D) at amino acid position 223 to be replaced by a tyrosine (Y). 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	0.77
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;D;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;M;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.1	D;D;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.075	T;T;T;T
Polyphen		0.42	.;B;.;.
Vest4		0.86
MVP		0.68
MPC		2.3
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1367068828; hg19: chr11-67166524;