Genetic Variant PPP1CB:c.521-139_521-138dupAA (chr2-28783757-G-GAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002709.3(PPP1CB):c.521-139_521-138dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 472,756 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 0.00014 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0051 ( 0 hom. )

Consequence

PPP1CB
NM_002709.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.164

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 20 AD gene.

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.521-139_521-138dupAA		intron	N/A	NP_002700.1	P62140
	PPP1CB	NM_206876.2		c.521-139_521-138dupAA		intron	N/A	NP_996759.1	P62140

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PPP1CB	ENST00000395366.3	TSL:1 MANE Select	c.521-150_521-149insAA	intron	N/A	ENSP00000378769.2	P62140
PPP1CB	ENST00000296122.10	TSL:1	c.521-150_521-149insAA	intron	N/A	ENSP00000296122.6	P62140
PPP1CB	ENST00000703174.1		c.644-150_644-149insAA	intron	N/A	ENSP00000515220.1	A0A8V8TRH9

Frequencies

GnomAD3 genomes

AF:

0.000142

AC:

AN:

141074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000248

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000202

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00506

AC:

1678

AN:

331682

Hom.:

AF XY:

0.00529

AC XY:

935

AN XY:

176656

show subpopulations

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

African (AFR)

AF:

0.0135

AC:

121

AN:

8958

American (AMR)

AF:

0.00488

AC:

AN:

14346

Ashkenazi Jewish (ASJ)

AF:

0.00489

AC:

AN:

9200

East Asian (EAS)

AF:

0.00676

AC:

148

AN:

21898

South Asian (SAS)

AF:

0.00698

AC:

226

AN:

32358

European-Finnish (FIN)

AF:

0.00532

AC:

110

AN:

20692

Middle Eastern (MID)

AF:

0.00305

AC:

AN:

1312

European-Non Finnish (NFE)

AF:

0.00421

AC:

861

AN:

204732

Other (OTH)

AF:

0.00511

AC:

AN:

18186

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.279

Heterozygous variant carriers

145

289

434

578

723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000142

AC:

AN:

141074

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

68088

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

38668

American (AMR)

AF:

0.00

AC:

AN:

14036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3318

East Asian (EAS)

AF:

0.00

AC:

AN:

4876

South Asian (SAS)

AF:

0.00

AC:

AN:

4540

European-Finnish (FIN)

AF:

0.000248

AC:

AN:

8080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000202

AC:

AN:

64458

Other (OTH)

AF:

0.00

AC:

AN:

1920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.16

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-28783757-GAAAA-GAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over