2-28783942-C-T

Variant names:

• chr2-28783942-C-T
• NM_002709.3:c.556C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002709.3(PPP1CB):​c.556C>T​(p.Arg186Trp) variant causes a missense change. 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: PPP1CB NM_002709.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• Publications: 0 publications found

Genes affected

PPP1CB (HGNC:9282): (protein phosphatase 1 catalytic subunit beta) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). 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. Mouse studies suggest that PP1 functions as a suppressor of learning and memory. Two alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

SPDYA (HGNC:30613): (speedy/RINGO cell cycle regulator family member A) Enables protein kinase activator activity and protein kinase binding activity. Involved in several processes, including G1/S transition of mitotic cell cycle; positive regulation of cell population proliferation; and positive regulation of protein kinase activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_002709.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002709.3. 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
	PPP1CB	NM_002709.3	MANE Select	c.556C>T	p.Arg186Trp	missense	Exon 5 of 8	NP_002700.1	P62140
	PPP1CB	NM_206876.2		c.556C>T	p.Arg186Trp	missense	Exon 6 of 9	NP_996759.1	P62140

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1CB	ENST00000395366.3	TSL:1 MANE Select	c.556C>T	p.Arg186Trp	missense	Exon 5 of 8	ENSP00000378769.2	P62140
	PPP1CB	ENST00000296122.10	TSL:1	c.556C>T	p.Arg186Trp	missense	Exon 6 of 9	ENSP00000296122.6	P62140
	PPP1CB	ENST00000703174.1		c.679C>T	p.Arg227Trp	missense	Exon 6 of 9	ENSP00000515220.1	A0A8V8TRH9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	4.5	H
PhyloP100		4.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.62		Gain of catalytic residue at M189 (P = 0.0084)
MVP		0.49
MPC		3.1
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.96
Mutation Taster		=2/98	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

hg19: chr2-29006808; COSMIC: COSV56092247; COSMIC: COSV56092247;