Genetic Variant NM_002709.3:c.34A>T (chr2-28752158-A-T) – 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.34A>T(p.Ile12Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,396,004 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I12V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

PPP1CB
NM_002709.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.89

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 Gene-Disease associations (from GenCC):

Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Noonan syndrome-like disorder with loose anagen hair 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp

PPP1CB 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.34A>T	p.Ile12Phe	missense_variant	Exon 1 of 8	ENST00000395366.3	NP_002700.1	P62140V9HW04
PPP1CB	NM_206876.2 link	c.34A>T	p.Ile12Phe	missense_variant	Exon 2 of 9		NP_996759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1CB	ENST00000395366.3 link	c.34A>T	p.Ile12Phe	missense_variant	Exon 1 of 8	1	NM_002709.3	ENSP00000378769.2		P62140

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688570

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31036

American (AMR)

AF:

0.00

AC:

AN:

35612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25076

East Asian (EAS)

AF:

0.00

AC:

AN:

35232

South Asian (SAS)

AF:

0.00

AC:

AN:

79204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077394

Other (OTH)

AF:

0.00

AC:

AN:

57866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

.;T;D;D;D

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.46

LIST_S2

Pathogenic

0.99

D;D;D;.;.

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

4.1

.;.;H;H;H

PhyloP100

3.9

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-3.0

D;D;D;D;D

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.23

.;.;B;B;B

Vest4

0.37, 0.36

MutPred

0.65

Loss of stability (P = 0.1969);Loss of stability (P = 0.1969);Loss of stability (P = 0.1969);Loss of stability (P = 0.1969);Loss of stability (P = 0.1969);

MVP

0.65

MPC

3.1

ClinPred

0.99

GERP RS

4.7

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.74

gMVP

1.0

Mutation Taster

=41/59

disease causing

(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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NM_002709.3:c.34A>T

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