Genetic Variant PPP1R21:p.Glu95Glu (chr2-48458137-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001135629.3(PPP1R21):c.285A>G(p.Glu95Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,609,666 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

PPP1R21
NM_001135629.3 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.775

Publications

0 publications found

Variant links:

Genes affected

PPP1R21 (HGNC:30595): (protein phosphatase 1 regulatory subunit 21) Located in early endosome. [provided by Alliance of Genome Resources, Apr 2022]

PPP1R21 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P

PPP1R21 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 2-48458137-A-G is Benign according to our data. Variant chr2-48458137-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3053103.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.775 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00138 (210/152356) while in subpopulation AFR AF = 0.00467 (194/41578). AF 95% confidence interval is 0.00413. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R21	NM_001135629.3 link	c.285A>G	p.Glu95Glu	synonymous_variant	Exon 4 of 22	ENST00000294952.13	NP_001129101.1	Q6ZMI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R21	ENST00000294952.13 link	c.285A>G	p.Glu95Glu	synonymous_variant	Exon 4 of 22	1	NM_001135629.3	ENSP00000294952.8		Q6ZMI0-1

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

209

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000323

AC:

AN:

251108

AF XY:

0.000265

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000134

AC:

195

AN:

1457310

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

725212

show subpopulations

African (AFR)

AF:

0.00447

AC:

149

AN:

33352

American (AMR)

AF:

0.000336

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108518

Other (OTH)

AF:

0.000448

AC:

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00138

AC:

210

AN:

152356

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00467

AC:

194

AN:

41578

American (AMR)

AF:

0.000784

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000675

Hom.:

Bravo

AF:

0.00156

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PPP1R21-related disorder

Benign:1

Aug 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

BayesDel_noAF

Benign

-0.52

CADD

Benign

4.8

(source)

DANN

Benign

0.39

PhyloP100

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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2-48458137-A-G

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