2-28752151-C-T

Position:

chr2-28752151-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BP4BP7

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

Scores

Clinical Significance

Benign reviewed by expert panel B:6

Conservation

PhyloP100: 0.163

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]

PPP1CB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

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 linkuse as main transcript	c.27C>T	p.Asp9=	synonymous_variant	1/8	ENST00000395366.3	NP_002700.1
PPP1CB	NM_206876.2 linkuse as main transcript	c.27C>T	p.Asp9=	synonymous_variant	2/9		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3 linkuse as main transcript	c.27C>T	p.Asp9=	synonymous_variant	1/8	1	NM_002709.3	ENSP00000378769	P1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152114

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00120

AC XY:

AN XY:

78876

show subpopulations

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.:

Cov.:

AF XY:

0.00195

AC XY:

1344

AN XY:

688926

show subpopulations

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.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74432

show subpopulations

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.:

Bravo

AF:

0.00138

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

LINK: link

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over