6-43007966-G-C

Variant names:

• chr6-43007966-G-C
• rs1131691266
• NM_006245.4:c.758G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006245.4(PPP2R5D):​c.758G>C​(p.Arg253Pro) 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. R253Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 10.0
• Publications: 6 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_006245.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-43007966-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 429222.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 6-43007966-G-C is Pathogenic according to our data. Variant chr6-43007966-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 984827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.758G>C	p.Arg253Pro	missense_variant	Exon 7 of 16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.662G>C	p.Arg221Pro	missense_variant	Exon 7 of 16		NP_851307.1
PPP2R5D	NM_180977.3	c.440G>C	p.Arg147Pro	missense_variant	Exon 5 of 14		NP_851308.1
PPP2R5D	NM_001270476.2	c.305G>C	p.Arg102Pro	missense_variant	Exon 7 of 16		NP_001257405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.758G>C	p.Arg253Pro	missense_variant	Exon 7 of 16	1	NM_006245.4	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	c.662G>C	p.Arg221Pro	missense_variant	Exon 7 of 16	1		ENSP00000377669.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hogue-Janssens syndrome 1 Pathogenic:2

Jan 01, 2025

Center of Human Genetics, Hôpital Erasme

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2019

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-02-01 and interpreted as Pathogenic. Variant was initially reported on 2018-01-05 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

not provided Pathogenic:1 Other:1

Aug 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, including significantly impaired substrate binding (PMID: 36216457); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36216457) -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Likely pathogenic and reported on 11-09-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Neurodevelopmental abnormality Pathogenic:1

Aug 21, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS3 (PMID: 36216457), PS4_Supporting, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	4.2	H;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.87
MutPred		0.88		Gain of catalytic residue at P252 (P = 0.0174);.;.;.;
MVP		0.87
MPC		2.8
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1131691266; hg19: chr6-42975704;