1-202442551-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002481.4(PPP1R12B):c.1646A>G(p.Tyr549Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 1,612,818 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: PPP1R12B NM_002481.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.51

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008294284).
• BP6: Variant 1-202442551-A-G is Benign according to our data. Variant chr1-202442551-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2639789.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 383 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R12B	NM_002481.4	c.1646A>G	p.Tyr549Cys	missense_variant	12/24	ENST00000608999.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R12B	ENST00000608999.6	c.1646A>G	p.Tyr549Cys	missense_variant	12/24	1	NM_002481.4	A2
PPP1R12B	ENST00000391959.5	c.1646A>G	p.Tyr549Cys	missense_variant	12/25	5		P3
PPP1R12B	ENST00000704899.1	c.1646A>G	p.Tyr549Cys	missense_variant	12/24
PPP1R12B	ENST00000434615.2	c.26A>G	p.Tyr9Cys	missense_variant, NMD_transcript_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 383 AN: 151960 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00891

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000667 AC: 167 AN: 250342 Hom.: 0 AF XY: 0.000495 AC XY: 67 AN XY: 135330

Gnomad AFR exome AF: 0.00838

Gnomad AMR exome AF: 0.000380

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000654

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000236 AC: 345 AN: 1460746 Hom.: 4 Cov.: 30 AF XY: 0.000202 AC XY: 147 AN XY: 726702

Gnomad4 AFR exome AF: 0.00739

Gnomad4 AMR exome AF: 0.000428

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.00252 AC: 383 AN: 152072 Hom.: 3 Cov.: 32 AF XY: 0.00233 AC XY: 173 AN XY: 74264

Gnomad4 AFR AF: 0.00889

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000500 Hom.: 0

Bravo AF: 0.00274

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000774 AC: 94

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

PPP1R12B: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Pathogenic	0.28
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.084
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.16	T;T
Polyphen		0.0070	.;B
Vest4		0.56
MVP		0.51
MPC		0.21
ClinPred		0.019	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.18

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: rs142827848; hg19: chr1-202411679;