2-28752137-G-C

Variant names:

• chr2-28752137-G-C
• rs1158082133
• NM_002709.3:c.13G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002709.3(PPP1CB):​c.13G>C​(p.Glu5Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000286 in 1,397,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. E5E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.14
• 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]

PPP1CB Gene-Disease associations (from GenCC):

• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome-like disorder with loose anagen hair 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26110253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CB	NM_002709.3	c.13G>C	p.Glu5Gln	missense_variant	Exon 1 of 8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2	c.13G>C	p.Glu5Gln	missense_variant	Exon 2 of 9		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.13G>C	p.Glu5Gln	missense_variant	Exon 1 of 8	1	NM_002709.3	ENSP00000378769.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000133 AC: 2 AN: 150402 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000813

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1397538 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689316

African (AFR) AF: 0.00 AC: 0 AN: 31292

American (AMR) AF: 0.0000841 AC: 3 AN: 35656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25134

East Asian (EAS) AF: 0.00 AC: 0 AN: 35482

South Asian (SAS) AF: 0.00 AC: 0 AN: 79216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078142

Other (OTH) AF: 0.0000173 AC: 1 AN: 57938

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 5 of the PPP1CB protein (p.Glu5Gln). This variant is present in population databases (no rsID available, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with PPP1CB-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	.;T;T;T;T
Eigen	Benign	-0.0064
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.97	D;D;D;.;.
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;.;L;L;L
PhyloP100		4.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.88	N;N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.028	D;D;D;D;D
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.0010	.;.;B;B;B
Vest4		0.26, 0.27
MutPred		0.20		Loss of disorder (P = 0.1795);Loss of disorder (P = 0.1795);Loss of disorder (P = 0.1795);Loss of disorder (P = 0.1795);Loss of disorder (P = 0.1795);
MVP		0.70
MPC		1.7
ClinPred		0.63	D
GERP RS		4.7
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		4.0
Varity_R		0.32
gMVP		0.79
Mutation Taster		=76/24	polymorphism

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

dbSNP: rs1158082133; hg19: chr2-28975003;