11-111727039-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_181699.3(PPP2R1B):​c.1930C>T​(p.Arg644Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 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: 0.000013 ( 0 hom. )

Consequence

PPP2R1B
NM_181699.3 missense

Scores

2
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97
Variant links:
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]
SIK2 (HGNC:21680): (salt inducible kinase 2) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in intracellular signal transduction and protein autophosphorylation. Predicted to be located in nucleus. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.104323536).
BS2
High AC in GnomAdExome4 at 19 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
SIK2NM_015191.3 linkuse as main transcriptc.*2910G>A 3_prime_UTR_variant 15/15 ENST00000304987.4 NP_056006.1 Q9H0K1A0A024R3G7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PPP2R1BENST00000311129.9 linkuse as main transcriptc.1930C>T p.Arg644Cys missense_variant 16/161 ENSP00000311344.5 P30154-2
SIK2ENST00000304987.4 linkuse as main transcriptc.*2910G>A 3_prime_UTR_variant 15/151 NM_015191.3 ENSP00000305976.3 Q9H0K1
PPP2R1BENST00000530787.1 linkuse as main transcriptn.62C>T non_coding_transcript_exon_variant 2/21
PPP2R1BENST00000426998.6 linkuse as main transcriptc.1738C>T p.Arg580Cys missense_variant 14/142 ENSP00000410671.2 P30154-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
250980
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135652
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461748
Hom.:
0
Cov.:
30
AF XY:
0.0000193
AC XY:
14
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 14, 2023The c.1930C>T (p.R644C) alteration is located in exon 16 (coding exon 16) of the PPP2R1B gene. This alteration results from a C to T substitution at nucleotide position 1930, causing the arginine (R) at amino acid position 644 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
18
DANN
Benign
0.95
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.60
T;T
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.10
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.090
N;N
REVEL
Benign
0.074
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.014
D;D
Polyphen
0.0
B;.
Vest4
0.23
MutPred
0.38
Loss of disorder (P = 0.0402);.;
MVP
0.47
MPC
0.36
ClinPred
0.97
D
GERP RS
2.5
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.18
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759984147; hg19: chr11-111597763; API