rs886037955

Variant names:

• chr2-28793938-G-A
• rs886037955
• NM_002709.3:c.820G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP2 PS2 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.820G>A (p.Glu274Lys) variant in PP1CB is a missense variant predicted to cause substitution of glutamate by lysine at amino acid 274. This variant is absent from gnomAD v2 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP (PP2). This variant was observed in 2 probands with phenotypes consistent with RASopathy (PS4_Supporting; PMID:27681385, GeneDx). This variant has also been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:27681385). In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PP2, PS4_Supporting, PM2_Supporting. (RASopathy VCEP specifications version 1.3; 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586686/MONDO:0021060/128

• Frequency: Genomes: not found (cov: 33)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 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 Likely_pathogenic. Variant got 7 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.820G>A	p.Glu274Lys	missense_variant	Exon 7 of 8	1	NM_002709.3	ENSP00000378769.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

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

May 31, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 07, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

RASopathy Pathogenic:1

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.820G>A (p.Glu274Lys) variant in PP1CB is a missense variant predicted to cause substitution of glutamate by lysine at amino acid 274. This variant is absent from gnomAD v2 (PM2_Supporting). PPP1CB, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease. The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP (PP2). This variant was observed in 2 probands with phenotypes consistent with RASopathy (PS4_Supporting; PMID:27681385, GeneDx). This variant has also been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:27681385). In summary, this variant currently meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PP2, PS4_Supporting, PM2_Supporting. (RASopathy VCEP specifications version 1.3; 12/3/2024) -

PPP1CB-related disorder Uncertain:1

Feb 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
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;