19-52220677-C-T

Variant names:

• chr19-52220677-C-T
• rs8100500
• NM_014225.6:c.1364-302C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014225.6(PPP2R1A):​c.1364-302C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,006 control chromosomes in the GnomAD database, including 2,478 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2478 hom., cov: 32)
• Consequence: PPP2R1A NM_014225.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.881
• Publications: 6 publications found

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]

PPP2R1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Houge-Janssens syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Illumina, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014225.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	NM_014225.6	MANE Select	c.1364-302C>T		intron	N/A	NP_055040.2
	PPP2R1A	NM_001363656.2		c.827-302C>T		intron	N/A	NP_001350585.1
	PPP2R1A	NR_033500.2		n.1308-302C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP2R1A	ENST00000322088.11	TSL:1 MANE Select	c.1364-302C>T		intron	N/A	ENSP00000324804.6
	PPP2R1A	ENST00000454220.7	TSL:1	c.1484-302C>T		intron	N/A	ENSP00000391905.3
	PPP2R1A	ENST00000703398.1		c.1406-302C>T		intron	N/A	ENSP00000515288.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26763 AN: 151888 Hom.: 2469 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.161

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.176 AC: 26828 AN: 152006 Hom.: 2478 Cov.: 32 AF XY: 0.175 AC XY: 13032 AN XY: 74280

African (AFR) AF: 0.240 AC: 9943 AN: 41432

American (AMR) AF: 0.137 AC: 2092 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 560 AN: 3468

East Asian (EAS) AF: 0.116 AC: 600 AN: 5172

South Asian (SAS) AF: 0.110 AC: 530 AN: 4816

European-Finnish (FIN) AF: 0.180 AC: 1900 AN: 10546

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10726 AN: 67966

Other (OTH) AF: 0.161 AC: 340 AN: 2112

Alfa AF: 0.155 Hom.: 3582

Bravo AF: 0.176

Asia WGS AF: 0.131 AC: 458 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.76
DANN	Benign	0.48
PhyloP100		-0.88
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8100500; hg19: chr19-52723930;