10-73495883-C-T

Variant names:

• chr10-73495883-C-T
• rs2057216990
• NM_021132.4:c.7G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021132.4(PPP3CB):​c.7G>A​(p.Ala3Thr) 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. 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. A3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP3CB NM_021132.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15084395).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CB	NM_021132.4	MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 1 of 14	NP_066955.1	P16298-1
	PPP3CB	NM_001142353.3		c.7G>A	p.Ala3Thr	missense	Exon 1 of 14	NP_001135825.1	P16298-4
	PPP3CB	NM_001142354.3		c.7G>A	p.Ala3Thr	missense	Exon 1 of 13	NP_001135826.1	P16298-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CB	ENST00000360663.10	TSL:1 MANE Select	c.7G>A	p.Ala3Thr	missense	Exon 1 of 14	ENSP00000353881.5	P16298-1
	PPP3CB	ENST00000394829.6	TSL:1	c.7G>A	p.Ala3Thr	missense	Exon 1 of 14	ENSP00000378306.2	P16298-4
	PPP3CB	ENST00000394828.6	TSL:1	c.7G>A	p.Ala3Thr	missense	Exon 1 of 13	ENSP00000378305.2	P16298-3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000107 AC: 1 AN: 935708 Hom.: 0 Cov.: 25 AF XY: 0.00000218 AC XY: 1 AN XY: 458660

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

African (AFR) AF: 0.00 AC: 0 AN: 17710

American (AMR) AF: 0.00 AC: 0 AN: 5646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10312

East Asian (EAS) AF: 0.00 AC: 0 AN: 14530

South Asian (SAS) AF: 0.00 AC: 0 AN: 47240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2368

European-Non Finnish (NFE) AF: 0.00000128 AC: 1 AN: 784278

Other (OTH) AF: 0.00 AC: 0 AN: 35670

⚠️ 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.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.11	N
REVEL	Benign	0.072
Sift	Benign	0.070	T
Sift4G	Benign	0.10	T
Polyphen		0.0080	B
Vest4		0.26
MutPred		0.29		Gain of glycosylation at A3 (P = 0.0014)
MVP		0.16
MPC		0.58
ClinPred		0.34	T
GERP RS		3.9
PromoterAI		-0.18	Neutral
Varity_R		0.14
gMVP		0.43
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs2057216990; hg19: chr10-75255641;