Genetic Variant PPP1CB:c.521-141_521-138dupAAAA (chr2-28783757-G-GAAAA) – 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_521-138dupAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 334,434 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 0.0 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Failed GnomAD Quality Control

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: 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_521-138dupAAAA		intron_variant	Intron 4 of 7	ENST00000395366.3	NP_002700.1	P62140V9HW04
PPP1CB	NM_206876.2 link	c.521-141_521-138dupAAAA		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.521-150_521-149insAAAA		intron_variant	Intron 4 of 7	1	NM_002709.3	ENSP00000378769.2		P62140

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

141090

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000299

AC:

AN:

334434

Hom.:

AF XY:

0.00000561

AC XY:

AN XY:

178122

show subpopulations

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

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:

0.0000306

AC:

AN:

32686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1322

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

206348

Other (OTH)

AF:

0.00

AC:

AN:

18330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

141090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68096

African (AFR)

AF:

0.00

AC:

AN:

38674

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:

0.00

AC:

AN:

8084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64464

Other (OTH)

AF:

0.00

AC:

AN:

1920

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.16

Splicing

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

Publications

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2-28783757-GAAAA-GAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over