Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_006245.4(PPP2R5D):c.592G>A(p.Glu198Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

PPP2R5D
NM_006245.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:31O:1

Conservation

PhyloP100: 10.0

Publications

46 publications found

Variant links:

Genes affected

PPP2R5D (HGNC:9312): (protein phosphatase 2 regulatory subunit B'delta) The product of this gene belongs to the phosphatase 2A regulatory subunit B family. Protein phosphatase 2A 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 B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a delta isoform of the regulatory subunit B56 subfamily. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

PPP2R5D Gene-Disease associations (from GenCC):

Hogue-Janssens syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

PPP2R5D links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006245.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

PP5

Variant 6-43007265-G-A is Pathogenic according to our data. Variant chr6-43007265-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 190286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PPP2R5D	NM_006245.4	MANE Select	c.592G>A	p.Glu198Lys	missense	Exon 5 of 16	NP_006236.1
PPP2R5D	NM_180976.3		c.496G>A	p.Glu166Lys	missense	Exon 5 of 16	NP_851307.1
PPP2R5D	NM_180977.3		c.274G>A	p.Glu92Lys	missense	Exon 3 of 14	NP_851308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PPP2R5D	ENST00000485511.6	TSL:1 MANE Select	c.592G>A	p.Glu198Lys	missense	Exon 5 of 16	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	TSL:1	c.496G>A	p.Glu166Lys	missense	Exon 5 of 16	ENSP00000377669.3
PPP2R5D	ENST00000470467.5	TSL:1	c.349G>A	p.Glu117Lys	missense	Exon 3 of 13	ENSP00000419756.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hogue-Janssens syndrome 1 (20)

not provided (7)

Global developmental delay (1)

Inborn genetic diseases (1)

Intellectual disability (1)

Neurodevelopmental delay (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

4.1

PhyloP100

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.91

MutPred

0.67

Gain of ubiquitination at E198 (P = 0.0048)

MVP

0.85

MPC

2.5

ClinPred

1.0

GERP RS

5.8

Varity_R

0.86

gMVP

0.67

Mutation Taster

=1/99

disease causing (ClinVar)

(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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rs863225082

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over