2-28752155-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002709.3(PPP1CB):c.31C>G(p.Leu11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L11L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 2.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PPP1CB
• BP4: Computational evidence support a benign effect (MetaRNN=0.18366593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1CB	NM_002709.3	c.31C>G	p.Leu11Val	missense_variant	1/8	ENST00000395366.3
PPP1CB	NM_206876.2	c.31C>G	p.Leu11Val	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1CB	ENST00000395366.3	c.31C>G	p.Leu11Val	missense_variant	1/8	1	NM_002709.3	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396272 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 688684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Noonan syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.10
Eigen_PC	Benign	0.063
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.94	D;D;D;.;.
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	0.42	N;N;N;N;N
REVEL	Benign	0.079
Sift	Benign	0.18	T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.0	.;.;B;B;B
Vest4		0.25, 0.25, 0.24
MutPred		0.46		Gain of MoRF binding (P = 0.1986);Gain of MoRF binding (P = 0.1986);Gain of MoRF binding (P = 0.1986);Gain of MoRF binding (P = 0.1986);Gain of MoRF binding (P = 0.1986);
MVP		0.44
MPC		1.7
ClinPred		0.53	D
GERP RS		4.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.9
Varity_R		0.19
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs960710587; hg19: chr2-28975021;