Genetic Variant PPP1CB:c.521-141_521-138delAAAA (chr2-28783757-GAAAA-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002709.3(PPP1CB):c.521-141_521-138delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000631 in 475,582 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000071 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

PPP1CB
NM_002709.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

Publications

0 publications found

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:

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]

SPDYA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1CB	NM_002709.3 link	c.521-141_521-138delAAAA		intron_variant	Intron 4 of 7	ENST00000395366.3	NP_002700.1	P62140V9HW04
PPP1CB	NM_206876.2 link	c.521-141_521-138delAAAA		intron_variant	Intron 5 of 8		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3 link	c.521-149_521-146delAAAA		intron_variant	Intron 4 of 7	1	NM_002709.3	ENSP00000378769.2		P62140

Frequencies

GnomAD3 genomes

AF:

0.00000709

AC:

AN:

141092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000220

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000598

AC:

AN:

334442

Hom.:

AF XY:

0.0000112

AC XY:

AN XY:

178124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9054

American (AMR)

AF:

0.00

AC:

AN:

14478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9276

East Asian (EAS)

AF:

0.00

AC:

AN:

22112

South Asian (SAS)

AF:

0.00

AC:

AN:

32686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1322

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

206356

Other (OTH)

AF:

0.000109

AC:

AN:

18328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000709

AC:

AN:

141140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68164

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

38758

American (AMR)

AF:

0.00

AC:

AN:

14052

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3318

East Asian (EAS)

AF:

0.00

AC:

AN:

4862

South Asian (SAS)

AF:

0.000221

AC:

AN:

4520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64454

Other (OTH)

AF:

0.00

AC:

AN:

1934

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=99/1

polymorphism

(source)

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

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2-28783757-GAAAA-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over