ENST00000454220.7:c.191C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000454220.7(PPP2R1A):c.191C>T(p.Pro64Leu) variant causes a missense change. The variant allele was found at a frequency of 0.031 in 1,227,742 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: 𝑓 0.023 ( 60 hom., cov: 33)

Exomes 𝑓: 0.032 ( 680 hom. )

Consequence

PPP2R1A
ENST00000454220.7 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 3.72

Publications

4 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005302608).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0232 (3531/152348) while in subpopulation NFE AF = 0.0375 (2552/68026). AF 95% confidence interval is 0.0363. There are 60 homozygotes in GnomAd4. There are 1630 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 3531 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R1A	NM_014225.6 link	c.78+113C>T		intron_variant	Intron 1 of 14	ENST00000322088.11	NP_055040.2	P30153A8K7B7
PPP2R1A	NR_033500.2 link	n.123+113C>T		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+113C>T		intron_variant	Intron 1 of 14	1	NM_014225.6	ENSP00000324804.6		P30153

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3530

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00656

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.0186

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.0224

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0375

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0220

AC:

2361

AN:

107370

AF XY:

0.0225

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.0120

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.000106

Gnomad FIN exome

AF:

0.0256

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0234

GnomAD4 exome

AF:

0.0321

AC:

34476

AN:

1075394

Hom.:

680

Cov.:

AF XY:

0.0322

AC XY:

17279

AN XY:

537418

show subpopulations

African (AFR)

AF:

0.00545

AC:

133

AN:

24408

American (AMR)

AF:

0.0120

AC:

347

AN:

28860

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

266

AN:

20008

East Asian (EAS)

AF:

0.0000894

AC:

AN:

33558

South Asian (SAS)

AF:

0.0144

AC:

973

AN:

67586

European-Finnish (FIN)

AF:

0.0277

AC:

1287

AN:

46402

Middle Eastern (MID)

AF:

0.0305

AC:

129

AN:

4228

European-Non Finnish (NFE)

AF:

0.0374

AC:

30057

AN:

803568

Other (OTH)

AF:

0.0274

AC:

1281

AN:

46776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1669

3337

5006

6674

8343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

978

1956

2934

3912

4890

<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:

0.0232

AC:

3531

AN:

152348

Hom.:

Cov.:

AF XY:

0.0219

AC XY:

1630

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00654

AC:

272

AN:

41600

American (AMR)

AF:

0.0186

AC:

285

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00994

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0224

AC:

238

AN:

10628

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0375

AC:

2552

AN:

68026

Other (OTH)

AF:

0.0185

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

191

382

572

763

954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0269

Hom.:

Bravo

AF:

0.0223

TwinsUK

AF:

0.0380

AC:

141

ALSPAC

AF:

0.0384

AC:

148

ExAC

AF:

0.0136

AC:

363

Asia WGS

AF:

0.00837

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

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.71

PhyloP100

3.7

PROVEAN

Benign

0.020

REVEL

Benign

0.23

Sift

Uncertain

0.021

Sift4G

Pathogenic

0.0

ClinPred

0.10

GERP RS

5.0

PromoterAI

-0.0067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=90/10

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