11-111737492-T-A

Position:

• chr11-111737492-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The ENST00000311129.9(PPP2R1B):​c.1867A>T​(p.Asn623Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00726 in 1,614,200 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (67 hom.)
• Consequence: PPP2R1B ENST00000311129.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.86

Genes affected

PPP2R1B (HGNC:9303): (protein phosphatase 2 scaffold subunit Abeta) 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 a beta isoform of the constant regulatory subunit A. Mutations in this gene have been associated with some lung and colon cancers. Alternatively spliced transcript variants have been described. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037582517).
• BP6: Variant 11-111737492-T-A is Benign according to our data. Variant chr11-111737492-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2642364.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 975 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R1B	NM_181699.3	c.1867A>T	p.Asn623Tyr	missense_variant	15/16		NP_859050.1
PPP2R1B	NM_181700.2	c.1675A>T	p.Asn559Tyr	missense_variant	13/14		NP_859051.1
PPP2R1B	XM_047427196.1	c.1867A>T	p.Asn623Tyr	missense_variant	15/16		XP_047283152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R1B	ENST00000311129.9	c.1867A>T	p.Asn623Tyr	missense_variant	15/16	1		ENSP00000311344	A2
PPP2R1B	ENST00000526287.1	n.12A>T		non_coding_transcript_exon_variant	1/2	1
PPP2R1B	ENST00000426998.6	c.1675A>T	p.Asn559Tyr	missense_variant	13/14	2		ENSP00000410671

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 978 AN: 152194 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00570 AC: 1434 AN: 251470 Hom.: 5 AF XY: 0.00561 AC XY: 762 AN XY: 135908

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00935

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00735 AC: 10744 AN: 1461888 Hom.: 67 Cov.: 31 AF XY: 0.00730 AC XY: 5309 AN XY: 727244

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.00356

Gnomad4 NFE exome AF: 0.00865

Gnomad4 OTH exome AF: 0.00687

GnomAD4 genome AF: 0.00640 AC: 975 AN: 152312 Hom.: 10 Cov.: 33 AF XY: 0.00619 AC XY: 461 AN XY: 74476

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00874 Hom.: 4

Bravo AF: 0.00643

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00566 AC: 687

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00976

EpiControl AF: 0.0110

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

PPP2R1B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

PPP2R1B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	0.010
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.83	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.094
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.96	D;.
Vest4		0.41
MVP		0.47
MPC		0.34
ClinPred		0.023	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.23

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: rs61756429; hg19: chr11-111608216;