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):

• 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)

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R5D	NM_006245.4	MANE Select	c.758G>C	p.Arg253Pro	missense	Exon 7 of 16	NP_006236.1	Q14738-1
	PPP2R5D	NM_180976.3		c.662G>C	p.Arg221Pro	missense	Exon 7 of 16	NP_851307.1	Q14738-2
	PPP2R5D	NM_180977.3		c.440G>C	p.Arg147Pro	missense	Exon 5 of 14	NP_851308.1	Q14738-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R5D	ENST00000485511.6	TSL:1 MANE Select	c.758G>C	p.Arg253Pro	missense	Exon 7 of 16	ENSP00000417963.1	Q14738-1
	PPP2R5D	ENST00000394110.7	TSL:1	c.662G>C	p.Arg221Pro	missense	Exon 7 of 16	ENSP00000377669.3	Q14738-2
	PPP2R5D	ENST00000470467.5	TSL:1	c.515G>C	p.Arg172Pro	missense	Exon 5 of 13	ENSP00000419756.1	H0Y8C4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hogue-Janssens syndrome 1 (2)
1	-	-	Neurodevelopmental abnormality (1)
1	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		10
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	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;