dbSNP rs863225080: PPP2R5D:p.Glu420Lys (chr6-43009328-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_006245.4(PPP2R5D):c.1258G>A(p.Glu420Lys) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E420G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PPP2R5D
NM_006245.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 10.0

Publications

13 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):

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

PPP2R5D links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

PP5

Variant 6-43009328-G-A is Pathogenic according to our data. Variant chr6-43009328-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 217912.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	UniProt
PPP2R5D	NM_006245.4	MANE Select	c.1258G>A	p.Glu420Lys	missense	Exon 12 of 16	NP_006236.1	Q14738-1
PPP2R5D	NM_180976.3		c.1162G>A	p.Glu388Lys	missense	Exon 12 of 16	NP_851307.1	Q14738-2
PPP2R5D	NM_180977.3		c.940G>A	p.Glu314Lys	missense	Exon 10 of 14	NP_851308.1	Q14738-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PPP2R5D	ENST00000485511.6	TSL:1 MANE Select	c.1258G>A	p.Glu420Lys	missense	Exon 12 of 16	ENSP00000417963.1	Q14738-1
PPP2R5D	ENST00000394110.7	TSL:1	c.1162G>A	p.Glu388Lys	missense	Exon 12 of 16	ENSP00000377669.3	Q14738-2
PPP2R5D	ENST00000470467.5	TSL:1	c.961G>A	p.Glu321Lys	missense	Exon 9 of 13	ENSP00000419756.1	H0Y8C4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hogue-Janssens syndrome 1 (2)

Inborn genetic diseases (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

0.96

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

4.2

PhyloP100

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.97

MutPred

0.79

Gain of methylation at E420 (P = 0.0038)

MVP

0.83

MPC

2.5

ClinPred

1.0

GERP RS

6.0

PromoterAI

-0.26

Neutral

(source)

Varity_R

0.58

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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