6-42989623-G-A

Position:

• chr6-42989623-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006245.4(PPP2R5D):​c.40G>A​(p.Val14Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PPP2R5D NM_006245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.645

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.04555127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R5D	NM_006245.4	c.40G>A	p.Val14Ile	missense_variant	2/16	ENST00000485511.6	NP_006236.1
PPP2R5D	NM_180976.3	c.40G>A	p.Val14Ile	missense_variant	2/16		NP_851307.1
PPP2R5D	NM_001270476.2	c.-431G>A		5_prime_UTR_variant	2/16		NP_001257405.1
PPP2R5D	NM_180977.3	c.27+4919G>A		intron_variant			NP_851308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R5D	ENST00000485511.6	c.40G>A	p.Val14Ile	missense_variant	2/16	1	NM_006245.4	ENSP00000417963	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461452 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727036

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 14 of the PPP2R5D protein (p.Val14Ile). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.084
Sift	Benign	0.89	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.071
MutPred		0.15		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.19
MPC		0.96
ClinPred		0.52	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.033
gMVP		0.031

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

LitVar

Other links and lift over

dbSNP: rs1771109410; hg19: chr6-42957361;