rs149080732

Variant names:

• chr3-136002075-C-G
• rs149080732
• NM_002718.5:c.577C>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002718.5(PPP2R3A):​c.577C>G​(p.Leu193Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000474 in 1,614,094 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (3 hom.)
• Consequence: PPP2R3A NM_002718.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.904

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026659071).
• BP6: Variant 3-136002075-C-G is Benign according to our data. Variant chr3-136002075-C-G is described in ClinVar as [Benign]. Clinvar id is 3040470.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R3A	NM_002718.5	c.577C>G	p.Leu193Val	missense_variant	Exon 2 of 14	ENST00000264977.8	NP_002709.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R3A	ENST00000264977.8	c.577C>G	p.Leu193Val	missense_variant	Exon 2 of 14	1	NM_002718.5	ENSP00000264977.3
PPP2R3A	ENST00000490467.5	c.-213-24757C>G		intron_variant	Intron 1 of 12	2		ENSP00000419344.1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00151 AC: 379 AN: 251050 Hom.: 2 AF XY: 0.00133 AC XY: 180 AN XY: 135742

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0151

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000448 AC: 655 AN: 1461782 Hom.: 3 Cov.: 39 AF XY: 0.000446 AC XY: 324 AN XY: 727166

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.0113

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74468

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0126

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000997

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00141 AC: 171

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PPP2R3A-related disorder Benign:1

Sep 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.072
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.95	L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.019
Sift	Benign	0.092	T
Sift4G	Benign	0.14	T
Polyphen		0.26	B
Vest4		0.071
MVP		0.093
MPC		0.086
ClinPred		0.0048	T
GERP RS		3.5
Varity_R		0.055
gMVP		0.19

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: rs149080732; hg19: chr3-135720917;