Genetic Variant PPP4R2:p.Pro65Ala (chr3-73047262-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_174907.4(PPP4R2):c.193C>G(p.Pro65Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,455,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P65S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PPP4R2
NM_174907.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.82

Publications

0 publications found

Variant links:

Genes affected

PPP4R2 (HGNC:18296): (protein phosphatase 4 regulatory subunit 2) The protein encoded by this gene is a regulatory subunit of the serine/threonine-protein phosphatase 4 complex. In addition to being required for efficient DNA double strand break repair, this complex plays a role in organization of microtubules at centrosomes and processing of spliceosomal snRNPs. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

PPP4R2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP4R2	NM_174907.4 link	c.193C>G	p.Pro65Ala	missense_variant	Exon 3 of 9	ENST00000356692.10	NP_777567.1	Q9NY27-1
PPP4R2	NM_001318026.2 link	c.79C>G	p.Pro27Ala	missense_variant	Exon 3 of 9		NP_001304955.1	Q9NY27
PPP4R2	NM_001318025.2 link	c.117-11775C>G		intron_variant	Intron 2 of 7		NP_001304954.1	Q9NY27-2
PPP4R2	NM_001318027.2 link	c.-164-11775C>G		intron_variant	Intron 2 of 7		NP_001304956.1	Q9NY27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP4R2	ENST00000356692.10 link	c.193C>G	p.Pro65Ala	missense_variant	Exon 3 of 9	1	NM_174907.4	ENSP00000349124.5		Q9NY27-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000823

AC:

AN:

243130

AF XY:

0.0000152

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1455614

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33312

American (AMR)

AF:

0.00

AC:

AN:

44316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.00

AC:

AN:

85540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1107652

Other (OTH)

AF:

0.00

AC:

AN:

60156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.6

M;.;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.8

D;D;D

REVEL

Uncertain

0.51

Sift

Benign

0.054

T;T;D

Sift4G

Pathogenic

0.0

D;T;.

Polyphen

1.0

D;.;.

Vest4

0.65

MutPred

0.56

Loss of glycosylation at P70 (P = 0.0137);Loss of glycosylation at P70 (P = 0.0137);.;

MVP

0.40

MPC

0.21

ClinPred

0.93

GERP RS

5.5

Varity_R

0.48

gMVP

0.35

Mutation Taster

=10/90

disease causing

(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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chr3-73047262-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over