Genetic Variant PPP2R5D:p.Glu200Lys (chr6-43007271-G-A) – ACMG Classification: Pathogenic (14 pts)

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.598G>A(p.Glu200Lys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E200Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PPP2R5D
NM_006245.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24O:1

Conservation

PhyloP100: 9.95

Publications

28 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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006245.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.881

PP5

Variant 6-43007271-G-A is Pathogenic according to our data. Variant chr6-43007271-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217456.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.598G>A	p.Glu200Lys	missense	Exon 5 of 16	NP_006236.1
PPP2R5D	NM_180976.3		c.502G>A	p.Glu168Lys	missense	Exon 5 of 16	NP_851307.1
PPP2R5D	NM_180977.3		c.280G>A	p.Glu94Lys	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.598G>A	p.Glu200Lys	missense	Exon 5 of 16	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	TSL:1	c.502G>A	p.Glu168Lys	missense	Exon 5 of 16	ENSP00000377669.3
PPP2R5D	ENST00000470467.5	TSL:1	c.355G>A	p.Glu119Lys	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/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hogue-Janssens syndrome 1 (14)

not provided (9)

Inborn genetic diseases (1)

PPP2R5D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

4.1

PhyloP100

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.92

MutPred

0.73

Gain of ubiquitination at E200 (P = 0.0121)

MVP

0.83

MPC

2.2

ClinPred

1.0

GERP RS

5.7

Varity_R

0.78

gMVP

0.69

Mutation Taster

=0/100

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over