6-42984685-A-T

Position:

• chr6-42984685-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS2

The NM_006245.4(PPP2R5D):​c.8A>T​(p.Tyr3Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000048 in 1,459,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.66

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2R5D. . Gene score misZ 3.6476 (greater than the threshold 3.09). Trascript score misZ 4.9069 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, Hogue-Janssens syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32083628).
• BP6: Variant 6-42984685-A-T is Benign according to our data. Variant chr6-42984685-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1208150.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.8A>T	p.Tyr3Phe	missense_variant	1/16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.8A>T	p.Tyr3Phe	missense_variant	1/16		NP_851307.1
PPP2R5D	NM_180977.3	c.8A>T	p.Tyr3Phe	missense_variant	1/14		NP_851308.1
PPP2R5D	NM_001270476.2	c.-463A>T		5_prime_UTR_variant	1/16		NP_001257405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.8A>T	p.Tyr3Phe	missense_variant	1/16	1	NM_006245.4	ENSP00000417963	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459088 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 3 of the PPP2R5D protein (p.Tyr3Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PPP2R5D-related conditions. ClinVar contains an entry for this variant (Variation ID: 1208150). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Benign	0.019
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D;D;D;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.35	N;N;.;N
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.11	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.054	T;T;T;T
Sift4G	Uncertain	0.060	T;T;D;T
Polyphen		0.084	B;P;.;P
Vest4		0.57
MutPred		0.14		Loss of phosphorylation at Y3 (P = 0.0161);Loss of phosphorylation at Y3 (P = 0.0161);Loss of phosphorylation at Y3 (P = 0.0161);Loss of phosphorylation at Y3 (P = 0.0161);
MVP		0.52
MPC		1.2
ClinPred		0.52	D
GERP RS		5.2
Varity_R		0.17
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-42952423;