2-28783934-A-C

Position:

• chr2-28783934-A-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP2 PP5_Very_Strong

The NM_002709.3(PPP1CB):​c.548A>C​(p.Glu183Ala) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E183V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.29

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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-28783934-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 254651.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 2-28783934-A-C is Pathogenic according to our data. Variant chr2-28783934-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 254652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-28783934-A-C is described in Lovd as [Likely_pathogenic]. Variant chr2-28783934-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1CB	NM_002709.3	c.548A>C	p.Glu183Ala	missense_variant	5/8	ENST00000395366.3
PPP1CB	NM_206876.2	c.548A>C	p.Glu183Ala	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1CB	ENST00000395366.3	c.548A>C	p.Glu183Ala	missense_variant	5/8	1	NM_002709.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 183 of the PPP1CB protein (p.Glu183Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 27681385, 30236064). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 254652). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PPP1CB protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2021	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27681385, 30236064) -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 31, 2017

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2021

The c.548A>C (p.E183A) alteration is located in exon 5 (coding exon 5) of the PPP1CB gene. This alteration results from an A to C substitution at nucleotide position 548, causing the glutamic acid (E) at amino acid position 183 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the PPP1CB c.548A>C alteration was not observed, with coverage at this position. This alteration has been previously reported in multiple patients with various phenotypes suggestive of Noonan syndrome including global developmental delay, macrocephaly, seizures, congenital heart defects, and dysmorphic features (Ma, 2016; Lin, 2018; Hong 2020). In addition, another alteration affecting the same amino acid, p.E183V, was reported in a patient with a similar neurodevelopmental disorder (Ma, 2016). The p.E183 amino acid is conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The p.E183A alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;D;D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;.;.
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.078	T;T;T;T
Polyphen		0.014	.;B;B;B
Vest4		0.92, 0.92
MutPred		0.56		.;Loss of disorder (P = 0.0568);Loss of disorder (P = 0.0568);Loss of disorder (P = 0.0568);
MVP		0.81
MPC		2.2
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.64
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: rs886037954; hg19: chr2-29006800;