8-22475031-A-C

Variant names:

• chr8-22475031-A-C
• rs146307937
• NM_005605.5:c.127A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_005605.5(PPP3CC):​c.127A>C​(p.Lys43Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000226 in 1,613,190 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: PPP3CC NM_005605.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.00
• Publications: 0 publications found

Genes affected

PPP3CC (HGNC:9316): (protein phosphatase 3 catalytic subunit gamma) Calcineurin is a calcium-dependent, calmodulin-stimulated protein phosphatase involved in the downstream regulation of dopaminergic signal transduction. Calcineurin is composed of a regulatory subunit and a catalytic subunit. The protein encoded by this gene represents one of the regulatory subunits that has been found for calcineurin. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

PPP3CC Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008904636).
• BP6: Variant 8-22475031-A-C is Benign according to our data. Variant chr8-22475031-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 737660.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005605.5. 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
	PPP3CC	NM_005605.5	MANE Select	c.127A>C	p.Lys43Gln	missense	Exon 2 of 14	NP_005596.2
	PPP3CC	NM_001243974.2		c.127A>C	p.Lys43Gln	missense	Exon 2 of 15	NP_001230903.1	P48454-3
	PPP3CC	NM_001243975.2		c.127A>C	p.Lys43Gln	missense	Exon 2 of 13	NP_001230904.1	P48454-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP3CC	ENST00000240139.10	TSL:1 MANE Select	c.127A>C	p.Lys43Gln	missense	Exon 2 of 14	ENSP00000240139.5	P48454-1
	PPP3CC	ENST00000289963.12	TSL:1	c.127A>C	p.Lys43Gln	missense	Exon 2 of 13	ENSP00000289963.8	P48454-2
	PPP3CC	ENST00000968566.1		c.127A>C	p.Lys43Gln	missense	Exon 2 of 14	ENSP00000638625.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00384

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: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000390 AC: 98 AN: 251334 AF XY: 0.000294

Gnomad AFR exome AF: 0.00524

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1460902 Hom.: 1 Cov.: 30 AF XY: 0.000127 AC XY: 92 AN XY: 726806

African (AFR) AF: 0.00460 AC: 154 AN: 33460

American (AMR) AF: 0.000403 AC: 18 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111360

Other (OTH) AF: 0.000282 AC: 17 AN: 60350

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74468

African (AFR) AF: 0.00383 AC: 159 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000407 Hom.: 0

Bravo AF: 0.00141

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.0
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.24
Sift	Benign	0.054	T
Sift4G	Benign	0.11	T
Polyphen		0.25	B
Vest4		0.54
MVP		0.80
MPC		0.39
ClinPred		0.088	T
GERP RS		5.8
Varity_R		0.29
gMVP		0.74
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs146307937; hg19: chr8-22332544; COSMIC: COSV107269944; COSMIC: COSV107269944;