rs1114167429

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS2PP2PS4_SupportingPM2_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

Scores

9
4
6

Clinical Significance

Likely pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 10.0
Variant links:
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]

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ACMG classification

Classification made for transcript

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
PPP1CBNM_002709.3 linkc.166G>C p.Ala56Pro missense_variant 2/8 ENST00000395366.3 NP_002700.1 P62140V9HW04
PPP1CBNM_206876.2 linkc.166G>C p.Ala56Pro missense_variant 3/9 NP_996759.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PPP1CBENST00000395366.3 linkc.166G>C p.Ala56Pro missense_variant 2/81 NM_002709.3 ENSP00000378769.2 P62140

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
LINK: link

Submissions by phenotype

Noonan syndrome-like disorder with loose anagen hair 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 31, 2017- -
RASopathy Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelSep 17, 2024The 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1114167429; hg19: chr2-28999830; API