17-50136017-C-T

Position:

• chr17-50136017-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000612501.2(PPP1R9B):​c.2254G>A​(p.Glu752Lys) 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. 8/13 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1R9B ENST00000612501.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

Genes affected

PPP1R9B (HGNC:9298): (protein phosphatase 1 regulatory subunit 9B) This gene encodes a scaffold protein that functions as a regulatory subunit of protein phosphatase 1a. Expression of this gene is particularly high in dendritic spines, suggesting that the encoded protein may play a role in receiving signals from the central nervous system. The encoded protein has putative tumor suppressor function and decreased expression has been observed in tumors. [provided by RefSeq, Feb 2014]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1R9B	NM_032595.5	c.2254G>A	p.Glu752Lys	missense_variant	8/10	ENST00000612501.2	NP_115984.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R9B	ENST00000612501.2	c.2254G>A	p.Glu752Lys	missense_variant	8/10	1	NM_032595.5	ENSP00000478767	P1
	ENST00000451776.1	n.92+340C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

PPP1R9B-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

The PPP1R9B c.2254G>A variant is predicted to result in the amino acid substitution p.Ala752Thr. This variant has been detected with de novo occurrence in four large autism sequencing cohorts (described using hg19 coordinates 17:48213378:C:T or hg38 coordinates 17:50136013:C:T), but based on the patient ID#s given in the studies there are actually only two separate individuals being reported (Yuen et al. 2016. PubMed ID: 27525107, S3- Table S4; Satterstrom et al. 2020. PubMed ID: 31981491, Table S1; Fu et al. 2022. PubMed ID: 35982160, Supplementary Table 20; Zhou et al. 2022. PubMed ID: 35982159, Supp Data 1). This variant was also detected de novo in an internal case, but the phenotype was not consistent with PPP1R9B- related disease (Internal Data, PreventionGenetics). This variant is documented in one allele in gnomAD (0.0032% of alleles in individuals of Latino descent). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Benign	0.94
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.87	D
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.0060	D
Vest4		0.74
MVP		0.64
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.76

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: rs1359760756; hg19: chr17-48213382; COSMIC: COSV57541822; COSMIC: COSV57541822;