rs1114167429

Positions:

• chr2-28776964-G-C

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.166G>C (p.Ala56Pro) variant in PPP1CB is a missense variant predicted to cause substitution of alanine by proline at amino acid 56. This variant is absent from gnomAD v4 (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 (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.463, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:27264673). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID:27264673). In summary, this variant 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, PS4_P, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA346581171/MONDO:0021060/128

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• 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]

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/exons	MANE	Protein	UniProt
PPP1CB	NM_002709.3	c.166G>C	p.Ala56Pro	missense_variant	2/8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2	c.166G>C	p.Ala56Pro	missense_variant	3/9		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3	c.166G>C	p.Ala56Pro	missense_variant	2/8	1	NM_002709.3	ENSP00000378769.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

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

- -

RASopathy Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Sep 17, 2024

The c.166G>C (p.Ala56Pro) variant in PPP1CB is a missense variant predicted to cause substitution of alanine by proline at amino acid 56. This variant is absent from gnomAD v4 (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 (PP2). The missense Z-score is 4.33 which is above the threshold set by the Rasopathy VCEP. The computational predictor REVEL gives a score of 0.463, which is neither above nor below the thresholds predicting a damaging or benign impact on PPP1CB function. This variant has been reported in 1 proband with features of RASopathy (PS4_Supporting; PMID:27264673). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with features of RASopathy (PS2; PMID: 27264673). In summary, this variant 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, PS4_P, PM2_P, PP2. (RASopathy VCEP specifications version 1.1; 9/17/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	.;.;T;D;D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.;.
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.1	.;.;.;L;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Benign	0.25	T;T;T;T;T;T
Polyphen		0.83	.;.;.;P;P;P
Vest4		0.71
MutPred		0.63		.;Gain of glycosylation at A56 (P = 0.0231);Gain of glycosylation at A56 (P = 0.0231);Gain of glycosylation at A56 (P = 0.0231);Gain of glycosylation at A56 (P = 0.0231);Gain of glycosylation at A56 (P = 0.0231);
MVP		0.79
MPC		3.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.99

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: rs1114167429; hg19: chr2-28999830;