Genetic Variant PPP2R1A:p.Phe54Val (chr19-52190256-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000454220.7(PPP2R1A):c.160T>G(p.Phe54Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,469,822 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.018 ( 94 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 54 hom. )

Consequence

PPP2R1A
ENST00000454220.7 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.799

Publications

2 publications found

Variant links:

Genes affected

PPP2R1A (HGNC:9302): (protein phosphatase 2 scaffold subunit Aalpha) This gene encodes a constant regulatory subunit of protein phosphatase 2. Protein phosphatase 2 is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The constant regulatory subunit A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. This gene encodes an alpha isoform of the constant regulatory subunit A. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

PPP2R1A Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Houge-Janssens syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P

PPP2R1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0024425983).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6 link	c.78+82T>G		intron_variant	Intron 1 of 14	ENST00000322088.11	NP_055040.2	P30153A8K7B7
PPP2R1A	NR_033500.2 link	n.123+82T>G		intron_variant	Intron 1 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11 link	c.78+82T>G		intron_variant	Intron 1 of 14	1	NM_014225.6	ENSP00000324804.6		P30153

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2796

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0636

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00634

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.00393

AC:

507

AN:

129066

AF XY:

0.00335

show subpopulations

Gnomad AFR exome

AF:

0.0634

Gnomad AMR exome

AF:

0.00288

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000192

Gnomad OTH exome

AF:

0.00274

GnomAD4 exome

AF:

0.00179

AC:

2353

AN:

1317496

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1025

AN XY:

651004

show subpopulations

African (AFR)

AF:

0.0616

AC:

1798

AN:

29174

American (AMR)

AF:

0.00448

AC:

141

AN:

31486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23442

East Asian (EAS)

AF:

0.00

AC:

AN:

34230

South Asian (SAS)

AF:

0.000261

AC:

AN:

76520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47886

Middle Eastern (MID)

AF:

0.00393

AC:

AN:

5344

European-Non Finnish (NFE)

AF:

0.000109

AC:

111

AN:

1014410

Other (OTH)

AF:

0.00476

AC:

262

AN:

55004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0184

AC:

2804

AN:

152326

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1319

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0636

AC:

2642

AN:

41562

American (AMR)

AF:

0.00634

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68030

Other (OTH)

AF:

0.0194

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

138

275

413

550

688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0206

Hom.:

Bravo

AF:

0.0205

ExAC

AF:

0.00435

AC:

141

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.97

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

PhyloP100

0.80

PROVEAN

Benign

0.020

REVEL

Benign

0.017

Sift

Benign

0.079

Sift4G

Benign

0.072

MVP

0.57

ClinPred

0.035

GERP RS

2.3

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over