2-28793938-G-A

Position:

• chr2-28793938-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The ENST00000395366.3(PPP1CB):​c.820G>A​(p.Glu274Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP1CB ENST00000395366.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 10.0

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

Verdict is Uncertain_significance. Variant got 5 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.
• PP5: Variant 2-28793938-G-A is Pathogenic according to our data. Variant chr2-28793938-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 254653.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1CB	NM_002709.3	c.820G>A	p.Glu274Lys	missense_variant	7/8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2	c.820G>A	p.Glu274Lys	missense_variant	8/9		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.820G>A	p.Glu274Lys	missense_variant	7/8	1	NM_002709.3	ENSP00000378769	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome-like disorder with loose anagen hair 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 31, 2017

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2020

De novo variant with confirmed parentage in a patient with features of a PPP1CB-related disorder from the published literature (Ma et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27681385) -

PPP1CB-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The PPP1CB c.820G>A variant is predicted to result in the amino acid substitution p.Glu274Lys. This variant has been reported as de novo in an individual with the clinical features of short stature, developmental delay, congenital heart defects, toe syndactyly, and high-arched palate (Ma et al. 2016. PubMed ID: 27681385). This variant has also been reported in a large screen of the Turkish population in an individual with unknown phenotype (Table S4, Kars et al. 2021. PubMed ID: 34426522). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;.
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.62	P;P;P
Vest4		0.73
MutPred		0.55		Gain of methylation at E274 (P = 0.0036);Gain of methylation at E274 (P = 0.0036);Gain of methylation at E274 (P = 0.0036);
MVP		0.69
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886037955; hg19: chr2-29016804;