1-202416875-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002481.4(PPP1R12B):​c.380C>T​(p.Pro127Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PPP1R12B
NM_002481.4 missense

Scores

12
4
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90
Variant links:
Genes affected
PPP1R12B (HGNC:7619): (protein phosphatase 1 regulatory subunit 12B) Myosin phosphatase is a protein complex comprised of three subunits: a catalytic subunit (PP1c-delta, protein phosphatase 1, catalytic subunit delta), a large regulatory subunit (MYPT, myosin phosphatase target) and small regulatory subunit (sm-M20). Two isoforms of MYPT have been isolated--MYPT1 and MYPT2, the first of which is widely expressed, and the second of which may be specific to heart, skeletal muscle, and brain. Each of the MYPT isoforms functions to bind PP1c-delta and increase phosphatase activity. This locus encodes both MYTP2 and M20. Alternatively spliced transcript variants encoding different isoforms have been identified. Related pseudogenes have been defined on the Y chromosome. [provided by RefSeq, Oct 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PPP1R12BNM_002481.4 linkc.380C>T p.Pro127Leu missense_variant Exon 2 of 24 ENST00000608999.6 NP_002472.2 O60237-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PPP1R12BENST00000608999.6 linkc.380C>T p.Pro127Leu missense_variant Exon 2 of 24 1 NM_002481.4 ENSP00000476755.1 O60237-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461634
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
727122
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.380C>T (p.P127L) alteration is located in exon 2 (coding exon 2) of the PPP1R12B gene. This alteration results from a C to T substitution at nucleotide position 380, causing the proline (P) at amino acid position 127 to be replaced by a leucine (L). 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
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
.;T;.;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Benign
0.070
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.8
M;M;M;M
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-10
.;.;D;D
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
.;.;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
.;D;.;D
Vest4
0.95
MutPred
0.88
Loss of disorder (P = 0.0467);Loss of disorder (P = 0.0467);Loss of disorder (P = 0.0467);Loss of disorder (P = 0.0467);
MVP
0.95
MPC
1.9
ClinPred
0.98
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.72
gMVP
0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-202386003; API