Genetic Variant NM_021132.4:c.64G>A (chr10-73495826-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021132.4(PPP3CB):c.64G>A(p.Gly22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 929,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

PPP3CB
NM_021132.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.86

Publications

0 publications found

Variant links:

Genes affected

PPP3CB (HGNC:9315): (protein phosphatase 3 catalytic subunit beta) Enables several functions, including calmodulin binding activity; calmodulin-dependent protein phosphatase activity; and protein phosphatase 2B binding activity. Involved in calcineurin-NFAT signaling cascade; positive regulation of transcription by RNA polymerase II; and protein dephosphorylation. Located in cytoplasm. Part of calcineurin complex. Implicated in aortic valve stenosis. Biomarker of focal segmental glomerulosclerosis and schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

PPP3CB links:

PPP3CB-AS1 (HGNC:50750): (PPP3CB antisense RNA 1 (head to head))

PPP3CB-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21219322).

BS2

High AC in GnomAdExome4 at 55 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021132.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP3CB	NM_021132.4	MANE Select	c.64G>A	p.Gly22Arg	missense	Exon 1 of 14	NP_066955.1	P16298-1
PPP3CB	NM_001142353.3		c.64G>A	p.Gly22Arg	missense	Exon 1 of 14	NP_001135825.1	P16298-4
PPP3CB	NM_001142354.3		c.64G>A	p.Gly22Arg	missense	Exon 1 of 13	NP_001135826.1	P16298-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP3CB	ENST00000360663.10	TSL:1 MANE Select	c.64G>A	p.Gly22Arg	missense	Exon 1 of 14	ENSP00000353881.5	P16298-1
PPP3CB	ENST00000394829.6	TSL:1	c.64G>A	p.Gly22Arg	missense	Exon 1 of 14	ENSP00000378306.2	P16298-4
PPP3CB	ENST00000394828.6	TSL:1	c.64G>A	p.Gly22Arg	missense	Exon 1 of 13	ENSP00000378305.2	P16298-3

Frequencies

GnomAD3 genomes

AF:

0.0000142

AC:

AN:

140786

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000311

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000127

AC:

AN:

157854

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000281

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000697

AC:

AN:

789010

Hom.:

Cov.:

AF XY:

0.0000618

AC XY:

AN XY:

404804

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15260

American (AMR)

AF:

0.00

AC:

AN:

28734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13314

East Asian (EAS)

AF:

0.00

AC:

AN:

10992

South Asian (SAS)

AF:

0.00

AC:

AN:

70018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3306

European-Non Finnish (NFE)

AF:

0.0000886

AC:

AN:

586878

Other (OTH)

AF:

0.0000985

AC:

AN:

30460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000142

AC:

AN:

140904

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

68534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38950

American (AMR)

AF:

0.00

AC:

AN:

14356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3340

East Asian (EAS)

AF:

0.00

AC:

AN:

4110

South Asian (SAS)

AF:

0.00

AC:

AN:

3868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0000311

AC:

AN:

64314

Other (OTH)

AF:

0.00

AC:

AN:

1998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000714

Hom.:

ExAC

AF:

0.00000881

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

PhyloP100

2.9

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.070

REVEL

Benign

0.040

Sift

Uncertain

0.014

Sift4G

Benign

0.58

Polyphen

0.59

Vest4

0.38

MutPred

0.18

Gain of helix (P = 0.0425)

MVP

0.19

MPC

0.82

ClinPred

0.31

GERP RS

2.9

PromoterAI

-0.027

Neutral

(source)

Varity_R

0.20

gMVP

0.37

Mutation Taster

=88/12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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