2-28752151-C-T

Position:

• chr2-28752151-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1 BP4 BP7

This summary comes from the ClinGen Evidence Repository: The c.27C>T (p.Asp9=) variant in PPP1CB is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population minor allele frequency in gnomAD v4 is 0.002280 (2698/1145756 alleles) in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.1; 9/17/24) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1589147/MONDO:0021060/128

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: PPP1CB NM_002709.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: 0.163

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 Benign. Variant got -10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1CB	NM_002709.3	c.27C>T	p.Asp9=	synonymous_variant	1/8	ENST00000395366.3
PPP1CB	NM_206876.2	c.27C>T	p.Asp9=	synonymous_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1CB	ENST00000395366.3	c.27C>T	p.Asp9=	synonymous_variant	1/8	1	NM_002709.3	P1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152114 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00124 AC: 185 AN: 148954 Hom.: 0 AF XY: 0.00120 AC XY: 95 AN XY: 78876

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000368

Gnomad SAS exome AF: 0.0000881

Gnomad FIN exome AF: 0.000196

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.00141

GnomAD4 exome AF: 0.00196 AC: 2736 AN: 1396748 Hom.: 4 Cov.: 31 AF XY: 0.00195 AC XY: 1344 AN XY: 688926

Gnomad4 AFR exome AF: 0.000160

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000113

Gnomad4 SAS exome AF: 0.000101

Gnomad4 FIN exome AF: 0.000388

Gnomad4 NFE exome AF: 0.00235

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152230 Hom.: 1 Cov.: 30 AF XY: 0.00116 AC XY: 86 AN XY: 74432

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PPP1CB: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 20, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RASopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Sep 17, 2024

The c.27C>T (p.Asp9=) variant in PPP1CB is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by UCSC Genome Browser (BP4, BP7). The highest population minor allele frequency in gnomAD v4 is 0.002280 (2698/1145756 alleles) in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1, BP4, BP7. (RASopathy VCEP specifications version 1.1; 9/17/24) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.95
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9

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: rs141050112; hg19: chr2-28975017;