12-79786420-T-C

Position:

chr12-79786420-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002480.3(PPP1R12A):c.2861A>G(p.Asn954Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000173 in 1,564,348 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

PPP1R12A
NM_002480.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.95

Variant links:

Genes affected

PPP1R12A (HGNC:7618): (protein phosphatase 1 regulatory subunit 12A) Myosin phosphatase target subunit 1, which is also called the myosin-binding subunit of myosin phosphatase, is one of the subunits of myosin phosphatase. Myosin phosphatase regulates the interaction of actin and myosin downstream of the guanosine triphosphatase Rho. The small guanosine triphosphatase Rho is implicated in myosin light chain (MLC) phosphorylation, which results in contraction of smooth muscle and interaction of actin and myosin in nonmuscle cells. The guanosine triphosphate (GTP)-bound, active form of RhoA (GTP.RhoA) specifically interacted with the myosin-binding subunit (MBS) of myosin phosphatase, which regulates the extent of phosphorylation of MLC. Rho-associated kinase (Rho-kinase), which is activated by GTP. RhoA, phosphorylated MBS and consequently inactivated myosin phosphatase. Overexpression of RhoA or activated RhoA in NIH 3T3 cells increased phosphorylation of MBS and MLC. Thus, Rho appears to inhibit myosin phosphatase through the action of Rho-kinase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2009]

PPP1R12A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008347601).

BP6

Variant 12-79786420-T-C is Benign according to our data. Variant chr12-79786420-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2540686.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1R12A	NM_002480.3 linkuse as main transcript	c.2861A>G	p.Asn954Ser	missense_variant	22/25	ENST00000450142.7	NP_002471.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R12A	ENST00000450142.7 linkuse as main transcript	c.2861A>G	p.Asn954Ser	missense_variant	22/25	1	NM_002480.3	ENSP00000389168	P3	O14974-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000243

AC:

AN:

181294

Hom.:

AF XY:

0.000239

AC XY:

AN XY:

96216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000967

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000444

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000183

Gnomad OTH exome

AF:

0.00107

GnomAD4 exome

AF:

0.000178

AC:

252

AN:

1412070

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

130

AN XY:

697928

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000981

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000176

Gnomad4 OTH exome

AF:

0.000291

GnomAD4 genome

AF:

0.000118

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000210

Hom.:

Bravo

AF:

0.000310

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.000261

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.2861A>G (p.N954S) alteration is located in exon 22 (coding exon 22) of the PPP1R12A gene. This alteration results from a A to G substitution at nucleotide position 2861, causing the asparagine (N) at amino acid position 954 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

PPP1R12A: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.60

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;T;.;.

Eigen

Benign

-0.014

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;.;D;D;D

MetaRNN

Benign

0.0083

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

N;N;.;N;N

REVEL

Benign

0.11

Sift

Benign

0.063

T;T;.;T;T

Sift4G

Benign

0.095

T;T;T;D;T

Polyphen

0.0050

B;B;.;.;P

Vest4

0.13

MVP

0.63

MPC

0.10

ClinPred

0.12

GERP RS

4.7

Varity_R

0.17

gMVP

0.087

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

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