10-73438325-C-A

Position:

• chr10-73438325-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021132.4(PPP3CB):​c.1492G>T​(p.Ala498Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP3CB NM_021132.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085401446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP3CB	NM_021132.4	c.1492G>T	p.Ala498Ser	missense_variant	14/14	ENST00000360663.10	NP_066955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP3CB	ENST00000360663.10	c.1492G>T	p.Ala498Ser	missense_variant	14/14	1	NM_021132.4	ENSP00000353881.5
PPP3CB	ENST00000394829.6	c.1495G>T	p.Ala499Ser	missense_variant	14/14	1		ENSP00000378306.2
PPP3CB	ENST00000394828.6	c.1465G>T	p.Ala489Ser	missense_variant	13/13	1		ENSP00000378305.2
PPP3CB	ENST00000430762.6	c.481G>T	p.Ala161Ser	missense_variant	7/7	3		ENSP00000398022.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.1495G>T (p.A499S) alteration is located in exon 14 (coding exon 14) of the PPP3CB gene. This alteration results from a G to T substitution at nucleotide position 1495, causing the alanine (A) at amino acid position 499 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	25
DANN	Benign	0.87
DEOGEN2	Benign	0.081	T;.;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.41	N;N;N;.
REVEL	Benign	0.034
Sift	Benign	0.66	T;T;T;.
Sift4G	Benign	0.70	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.23
MutPred		0.15		Gain of phosphorylation at A498 (P = 0.0388);.;.;.;
MVP		0.27
MPC		0.58
ClinPred		0.35	T
GERP RS		5.7
Varity_R		0.063
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-75198083;