rs2732514

Variant names:

• chr4-101137685-C-T
• rs2732514
• NM_000944.5:c.260-28607G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000944.5(PPP3CA):​c.260-28607G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 151,954 control chromosomes in the GnomAD database, including 9,718 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (9718 hom., cov: 30)
• Consequence: PPP3CA NM_000944.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.728
• Publications: 5 publications found

Genes affected

PPP3CA (HGNC:9314): (protein phosphatase 3 catalytic subunit alpha) Enables several functions, including ATPase binding activity; calmodulin binding activity; and calmodulin-dependent protein phosphatase activity. Involved in several processes, including calcineurin-NFAT signaling cascade; peptidyl-serine dephosphorylation; and response to calcium ion. Located in several cellular components, including cytosol; dendritic spine; and nucleoplasm. Part of calcineurin complex. Colocalizes with cytoplasmic side of plasma membrane. Implicated in developmental and epileptic encephalopathy 91. Biomarker of focal segmental glomerulosclerosis and schizophrenia. [provided by Alliance of Genome Resources, Apr 2022]

PPP3CA Gene-Disease associations (from GenCC):

• arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• developmental and epileptic encephalopathy 91

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP3CA	NM_000944.5	c.260-28607G>A		intron_variant	Intron 2 of 13	ENST00000394854.8	NP_000935.1
PPP3CA	NM_001130691.2	c.260-28607G>A		intron_variant	Intron 2 of 12		NP_001124163.1
PPP3CA	NM_001130692.2	c.260-28607G>A		intron_variant	Intron 2 of 11		NP_001124164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP3CA	ENST00000394854.8	c.260-28607G>A		intron_variant	Intron 2 of 13	1	NM_000944.5	ENSP00000378323.3

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45691 AN: 151836 Hom.: 9700 Cov.: 30

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.267

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.301 AC: 45750 AN: 151954 Hom.: 9718 Cov.: 30 AF XY: 0.296 AC XY: 21960 AN XY: 74278

African (AFR) AF: 0.604 AC: 24998 AN: 41382

American (AMR) AF: 0.216 AC: 3295 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 838 AN: 3466

East Asian (EAS) AF: 0.305 AC: 1577 AN: 5166

South Asian (SAS) AF: 0.259 AC: 1244 AN: 4812

European-Finnish (FIN) AF: 0.117 AC: 1242 AN: 10588

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.174 AC: 11795 AN: 67964

Other (OTH) AF: 0.267 AC: 564 AN: 2114

Alfa AF: 0.209 Hom.: 4573

Bravo AF: 0.325

Asia WGS AF: 0.312 AC: 1084 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.64
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs2732514; hg19: chr4-102058842;