6-43006514-C-T

Variant names:

• chr6-43006514-C-T
• rs757369209
• NM_006245.4:c.157C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_006245.4(PPP2R5D):​c.157C>T​(p.Pro53Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P53L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.51
• Publications: 10 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-43006514-C-T is Pathogenic according to our data. Variant chr6-43006514-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217455.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.045615107). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 16		NP_851307.1
PPP2R5D	NM_001270476.2	c.-297C>T		5_prime_UTR_variant	Exon 3 of 16		NP_001257405.1
PPP2R5D	NM_180977.3	c.28-420C>T		intron_variant	Intron 1 of 13		NP_851308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 16	1	NM_006245.4	ENSP00000417963.1
PPP2R5D	ENST00000394110.7	c.157C>T	p.Pro53Ser	missense_variant	Exon 3 of 16	1		ENSP00000377669.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hogue-Janssens syndrome 1 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 03, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
PhyloP100		1.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.10	N;N;N
REVEL	Benign	0.056
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0080	B;B;.
Vest4		0.17
MutPred		0.27		Gain of phosphorylation at P53 (P = 0.0078);Gain of phosphorylation at P53 (P = 0.0078);.;
MVP		0.30
MPC		1.2
ClinPred		0.12	T
GERP RS		4.5
PromoterAI		0.066	Neutral
Varity_R		0.034
gMVP		0.27
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs757369209; hg19: chr6-42974252;