rs886037954

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-28783934-A-C
• chr2-28783934-A-T

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 7P and 1B. PS2 PP2 PM2_Supporting PS4_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The c.548A>C (p.Glu183Ala) variant in PPP1CB is a missense variant predicted to cause substitution of glutamate by alanine 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 (PP3). The computational predictor REVEL gives a score of 0.283, which is below the threshold of 0.3, does not predict a damaging effect on PPP1CB function (BP4). This variant was observed in a proband with a phenotype consistent with RASopathy (PS4_Supporting; PMID:30236064). This variant has also been identified as a de novo occurrence with confirmed parental relationships in 2 individuals with features of RASopathy (PS2_VeryStrong; PMIDs: 30236064, 27681385). Based on ACMG/AMP criteria, this variant has enough supporting evidence to be classified as uncertain significance; however, the RASopathy VCEP has upgraded this classification to pathogenic based on ClinGen policy. 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_VeryStrong, PS4_Supporting, PM2_Supporting, PP2, BP4. (RASopathy VCEP specifications version 1.3; 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586683/MONDO:0021060/128

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1CB NM_002709.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• 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 6 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.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002709.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1CB	NM_002709.3	MANE Select	c.548A>C	p.Glu183Ala	missense	Exon 5 of 8	NP_002700.1
	PPP1CB	NM_206876.2		c.548A>C	p.Glu183Ala	missense	Exon 6 of 9	NP_996759.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1CB	ENST00000395366.3	TSL:1 MANE Select	c.548A>C	p.Glu183Ala	missense	Exon 5 of 8	ENSP00000378769.2
	PPP1CB	ENST00000296122.10	TSL:1	c.548A>C	p.Glu183Ala	missense	Exon 6 of 9	ENSP00000296122.6
	PPP1CB	ENST00000703174.1		c.671A>C	p.Glu224Ala	missense	Exon 6 of 9	ENSP00000515220.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Noonan syndrome-like disorder with loose anagen hair 2 (2)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Noonan syndrome-like disorder with loose anagen hair (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.078	T
Polyphen		0.014	B
Vest4		0.92
MutPred		0.56		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
Mutation Taster		=0/100	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;