rs587777968

Positions:

• chr19-52190287-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The ENST00000454220.7(PPP2R1A):​c.191C>T​(p.Pro64Leu) variant causes a missense change. The variant allele was found at a frequency of 0.031 in 1,227,742 control chromosomes in the GnomAD database, including 740 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (60 hom., cov: 33)
  • Exomes 𝑓: 0.032 (680 hom.)
• Consequence: PPP2R1A ENST00000454220.7 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.72

Genes affected

PPP2R1A (HGNC:9302): (protein phosphatase 2 scaffold subunit Aalpha) This gene encodes a constant regulatory subunit of protein phosphatase 2. Protein phosphatase 2 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 constant regulatory subunit A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. This gene encodes an alpha isoform of the constant regulatory subunit A. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PPP2R1A. . Gene score misZ 4.4565 (greater than the threshold 3.09). Trascript score misZ 4.3877 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Houge-Janssens syndrome 2, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.005302608).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0232 (3531/152348) while in subpopulation NFE AF= 0.0375 (2552/68026). AF 95% confidence interval is 0.0363. There are 60 homozygotes in gnomad4. There are 1630 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 3531 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R1A	NM_014225.6	c.78+113C>T		intron_variant		ENST00000322088.11	NP_055040.2
PPP2R1A	NR_033500.2	n.123+113C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R1A	ENST00000322088.11	c.78+113C>T		intron_variant		1	NM_014225.6	ENSP00000324804	P4

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3530 AN: 152230 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.00656

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0375

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0220 AC: 2361 AN: 107370 Hom.: 51 AF XY: 0.0225 AC XY: 1278 AN XY: 56892

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.000106

Gnomad SAS exome AF: 0.0140

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0234

GnomAD4 exome AF: 0.0321 AC: 34476 AN: 1075394 Hom.: 680 Cov.: 14 AF XY: 0.0322 AC XY: 17279 AN XY: 537418

Gnomad4 AFR exome AF: 0.00545

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.0000894

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0374

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0232 AC: 3531 AN: 152348 Hom.: 60 Cov.: 33 AF XY: 0.0219 AC XY: 1630 AN XY: 74504

Gnomad4 AFR AF: 0.00654

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00994

Gnomad4 FIN AF: 0.0224

Gnomad4 NFE AF: 0.0375

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0282 Hom.: 24

Bravo AF: 0.0223

TwinsUK AF: 0.0380 AC: 141

ALSPAC AF: 0.0384 AC: 148

ExAC AF: 0.0136 AC: 363

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.23
Sift	Uncertain	0.021	D
Sift4G	Pathogenic	0.0	D
ClinPred		0.10	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs41275796; hg19: chr19-52693540; COSMIC: COSV59044728;