chr2-28752137-G-C

Position:

• chr2-28752137-G-C

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.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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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

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 in gene, where missense usually causes diseases (based on misZ statistic), PPP1CB. . Gene score misZ 4.3319 (greater than the threshold 3.09). Trascript score misZ 4.7349 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome-like disorder with loose anagen hair 2, Noonan syndrome-like disorder with loose anagen hair.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26110253).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.13G>C	p.Glu5Gln	missense_variant	1/8	1	NM_002709.3	ENSP00000378769	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000133 AC: 2 AN: 150402 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 79568

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000841

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: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This variant has not been reported in the literature in individuals affected with PPP1CB-related conditions. 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%). 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. 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. -

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
MutationTaster	Benign	0.99	D;D;D
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
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		4.0
Varity_R		0.32
gMVP		0.79

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: rs1158082133; hg19: chr2-28975003;