Genetic Variant PPP1R12C:p.Ala726Ser (chr19-55091894-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017607.4(PPP1R12C):c.2176G>T(p.Ala726Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PPP1R12C
NM_017607.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

Variant links:

Genes affected

PPP1R12C (HGNC:14947): (protein phosphatase 1 regulatory subunit 12C) The gene encodes a subunit of myosin phosphatase. The encoded protein regulates the catalytic activity of protein phosphatase 1 delta and assembly of the actin cytoskeleton. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

PPP1R12C links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028980672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R12C	NM_017607.4 link	c.2176G>T	p.Ala726Ser	missense_variant	Exon 20 of 22	ENST00000263433.8	NP_060077.1	Q9BZL4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R12C	ENST00000263433.8 link	c.2176G>T	p.Ala726Ser	missense_variant	Exon 20 of 22	1	NM_017607.4	ENSP00000263433.1		Q9BZL4-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000639

AC:

AN:

250286

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000764

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1460982

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726810

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2176G>T (p.A726S) alteration is located in exon 20 (coding exon 20) of the PPP1R12C gene. This alteration results from a G to T substitution at nucleotide position 2176, causing the alanine (A) at amino acid position 726 to be replaced by a serine (S). 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

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.023

T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

N;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.43

N;N

REVEL

Benign

0.093

Sift

Benign

0.40

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.82

P;.

Vest4

0.076

MutPred

0.12

Gain of phosphorylation at A726 (P = 0.0024);.;

MVP

0.28

MPC

1.0

ClinPred

0.10

GERP RS

4.0

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.075

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over