3-136003422-A-G

Position:

• chr3-136003422-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002718.5(PPP2R3A):​c.1924A>G​(p.Ser642Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 1,613,444 control chromosomes in the GnomAD database, including 75,959 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (5414 hom., cov: 32)
  • Exomes 𝑓: 0.30 (70545 hom.)
• Consequence: PPP2R3A NM_002718.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.36

Genes affected

PPP2R3A (HGNC:9307): (protein phosphatase 2 regulatory subunit B''alpha) This gene encodes one of the regulatory subunits of the protein phosphatase 2. Protein phosphatase 2 (formerly named type 2A) is one of the four major Ser/Thr phosphatases and is implicated in the negative control of cell growth and division. Protein phosphatase 2 holoenzymes are heterotrimeric proteins composed of a structural subunit A, a catalytic subunit C, and a regulatory subunit B. The regulatory subunit is encoded by a diverse set of genes that have been grouped into the B/PR55, B'/PR61, and B''/PR72 families. These different regulatory subunits confer distinct enzymatic specificities and intracellular localizations to the holozenzyme. The product of this gene belongs to the B'' family. The B'' family has been further divided into subfamilies. The product of this gene belongs to the alpha subfamily of regulatory subunit B''. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038633943).
• BP6: Variant 3-136003422-A-G is Benign according to our data. Variant chr3-136003422-A-G is described in ClinVar as [Benign]. Clinvar id is 3056776.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R3A	NM_002718.5	c.1924A>G	p.Ser642Gly	missense_variant	2/14	ENST00000264977.8	NP_002709.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R3A	ENST00000264977.8	c.1924A>G	p.Ser642Gly	missense_variant	2/14	1	NM_002718.5	ENSP00000264977	P3
PPP2R3A	ENST00000490467.5	c.-213-23410A>G		intron_variant		2		ENSP00000419344

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38640 AN: 151974 Hom.: 5417 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.240

GnomAD3 exomes AF: 0.262 AC: 65660 AN: 250754 Hom.: 9979 AF XY: 0.274 AC XY: 37127 AN XY: 135602

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.0230

Gnomad SAS exome AF: 0.315

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.303 AC: 442857 AN: 1461352 Hom.: 70545 Cov.: 39 AF XY: 0.305 AC XY: 222024 AN XY: 727000

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.344

Gnomad4 EAS exome AF: 0.0201

Gnomad4 SAS exome AF: 0.317

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.291

GnomAD4 genome AF: 0.254 AC: 38652 AN: 152092 Hom.: 5414 Cov.: 32 AF XY: 0.253 AC XY: 18777 AN XY: 74338

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.240

Alfa AF: 0.304 Hom.: 15552

Bravo AF: 0.243

TwinsUK AF: 0.320 AC: 1186

ALSPAC AF: 0.339 AC: 1307

ESP6500AA AF: 0.175 AC: 770

ESP6500EA AF: 0.315 AC: 2708

ExAC AF: 0.265 AC: 32217

Asia WGS AF: 0.165 AC: 577 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPP2R3A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.99	P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.033
Sift	Benign	0.16	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.057
ClinPred		0.0068	T
GERP RS		3.5
Varity_R		0.051
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs17197552; hg19: chr3-135722264; COSMIC: COSV53861584;