1-202427132-C-T

Variant names:

• chr1-202427132-C-T
• rs1418771033
• NM_002481.4:c.794C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002481.4(PPP1R12B):​c.794C>T​(p.Ala265Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP1R12B NM_002481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002481.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R12B	NM_002481.4	MANE Select	c.794C>T	p.Ala265Val	missense	Exon 5 of 24	NP_002472.2	O60237-1
	PPP1R12B	NM_001331029.2		c.794C>T	p.Ala265Val	missense	Exon 5 of 25	NP_001317958.1	O60237-6
	PPP1R12B	NM_001410283.1		c.794C>T	p.Ala265Val	missense	Exon 5 of 25	NP_001397212.1	A0A994J7P4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R12B	ENST00000608999.6	TSL:1 MANE Select	c.794C>T	p.Ala265Val	missense	Exon 5 of 24	ENSP00000476755.1	O60237-1
	PPP1R12B	ENST00000480184.5	TSL:1	c.794C>T	p.Ala265Val	missense	Exon 5 of 10	ENSP00000417159.1	O60237-5
	PPP1R12B	ENST00000356764.6	TSL:1	c.794C>T	p.Ala265Val	missense	Exon 5 of 9	ENSP00000349206.2	O60237-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461858 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.27	N
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.39
Sift	Benign	0.043	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.49		Gain of methylation at K263 (P = 0.1099)
MVP		0.76
MPC		0.69
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.40
gMVP		0.42
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs1418771033; hg19: chr1-202396260;