chr2-28783934-A-T

Variant names:

• chr2-28783934-A-T
• rs886037954
• NM_002709.3:c.548A>T

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PP2 PS4_Supporting PM2_Supporting PM5 PS2

This summary comes from the ClinGen Evidence Repository: The c.548A>T (p.Glu183Val) variant in PPP1CB is a missense variant predicted to cause substitution of glutamate by valine at amino acid 183. 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 a proband with a phenotype consistent with RASopathy (PS4_Supporting; PMID:27681385). 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). The variant occurs at the same amino acid residue as the PPP1CB c.548A>C (p.Glu183Ala) variant, which has been classified as pathogenic by the ClinGen RASOpathy VCEP (PM5). Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as likely pathogenic; however, the RASopathy VCEP has upgraded this classification to pathogenic based on ClinGen policy due to the strength of evidence for the PM5 code. In summary, this variant currently meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM5, PP2, PS4_Supporting, PM2_Supporting. (RASopathy VCEP specifications version 1.3; 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586684/MONDO:0021060/128

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.29
• Publications: 8 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]

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

Our verdict: Pathogenic. The variant received 9 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.
• PM5: 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.548A>T	p.Glu183Val	missense_variant	Exon 5 of 8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2	c.548A>T	p.Glu183Val	missense_variant	Exon 6 of 9		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.548A>T	p.Glu183Val	missense_variant	Exon 5 of 8	1	NM_002709.3	ENSP00000378769.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

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

Sep 08, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E183V variant in the PPP1CB gene has been observed in internal GeneDx whole exome sequencing data in association with developmental delay, congenital heart defect, dysmorphic features, and short stature. The E183V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E183V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E183V as a pathogenic variant. -

Cardiovascular phenotype Pathogenic:1

May 07, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.548A>T (p.E183V) alteration is located in exon 6 (coding exon 5) of the PPP1CB gene. This alteration results from a A to T substitution at nucleotide position 548, causing the glutamic acid (E) at amino acid position 183 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported to be de novo in an individual with features consistent with PPP1CB-related Noonan syndrome-like with loose anagen hair (Ma, 2016). Another variant at the same codon, c.548A>C (p.E183A), has been identified in individuals with features consistent with PPP1CB-related Noonan syndrome-like with loose anagen hair (Lin, 2018; Ambry internal data). This amino acid position is highly 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 in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

RASopathy Pathogenic:1

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.548A>T (p.Glu183Val) variant in PPP1CB is a missense variant predicted to cause substitution of glutamate by valine at amino acid 183. 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 a proband with a phenotype consistent with RASopathy (PS4_Supporting; PMID:27681385). 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). The variant occurs at the same amino acid residue as the PPP1CB c.548A>C (p.Glu183Ala) variant, which has been classified as pathogenic by the ClinGen RASOpathy VCEP (PM5). Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as likely pathogenic; however, the RASopathy VCEP has upgraded this classification to pathogenic based on ClinGen policy due to the strength of evidence for the PM5 code. In summary, this variant currently meets the criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: PS2, PM5, PP2, PS4_Supporting, PM2_Supporting. (RASopathy VCEP specifications version 1.3; 12/3/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;D;D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;.;.
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	.;M;M;M
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.18	.;B;B;B
Vest4		0.95, 0.95, 0.94
MutPred		0.57		.;Loss of disorder (P = 0.0175);Loss of disorder (P = 0.0175);Loss of disorder (P = 0.0175);
MVP		0.82
MPC		2.3
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.80
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs886037954; hg19: chr2-29006800; COSMIC: COSV56091954; COSMIC: COSV56091954;