4-8592889-G-C

Position:

• chr4-8592889-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001014447.3(CPZ):​c.56G>C​(p.Arg19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,531,574 control chromosomes in the GnomAD database, including 26,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (1787 hom., cov: 34)
  • Exomes 𝑓: 0.18 (24921 hom.)
• Consequence: CPZ NM_001014447.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.253

Genes affected

CPZ (HGNC:2333): (carboxypeptidase Z) This gene encodes a member of the metallocarboxypeptidase family. This enzyme displays carboxypeptidase activity towards substrates with basic C-terminal residues. It is most active at neutral pH and is inhibited by active site-directed inhibitors of metallocarboxypeptidases. Alternative splicing in the coding region results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

CPZ (HGNC:):

GPR78 (HGNC:4528): (G protein-coupled receptor 78) The protein encoded by this gene belongs to the G protein-coupled receptor family, which contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. This is an orphan receptor, which displays significant level of constitutive activity. Association analysis shows preliminary evidence for the involvement of this gene in susceptibility to bipolar affective disorder and schizophrenia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011938214).
• BP6: Variant 4-8592889-G-C is Benign according to our data. Variant chr4-8592889-G-C is described in ClinVar as [Benign]. Clinvar id is 3056352.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPZ	NM_001014447.3	c.56G>C	p.Arg19Pro	missense_variant	1/11	ENST00000360986.9	NP_001014447.2
CPZ	NM_003652.4	c.56G>C	p.Arg19Pro	missense_variant	1/10		NP_003643.3
CPZ	NM_001014448.3	c.-619G>C		5_prime_UTR_variant	1/11		NP_001014448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986.9	c.56G>C	p.Arg19Pro	missense_variant	1/11	1	NM_001014447.3	ENSP00000354255.4

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20699 AN: 152120 Hom.: 1783 Cov.: 34

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0460

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.141 AC: 17665 AN: 125018 Hom.: 1632 AF XY: 0.151 AC XY: 10349 AN XY: 68750

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.0682

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.0481

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.186

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.184 AC: 254255 AN: 1379334 Hom.: 24921 Cov.: 37 AF XY: 0.185 AC XY: 125809 AN XY: 680730

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.0739

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.0489

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.199

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.136 AC: 20710 AN: 152240 Hom.: 1787 Cov.: 34 AF XY: 0.135 AC XY: 10041 AN XY: 74428

Gnomad4 AFR AF: 0.0459

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0461

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.194

Gnomad4 OTH AF: 0.130

Alfa AF: 0.122 Hom.: 429

Bravo AF: 0.123

TwinsUK AF: 0.191 AC: 708

ALSPAC AF: 0.200 AC: 770

ESP6500AA AF: 0.0435 AC: 147

ESP6500EA AF: 0.146 AC: 1040

ExAC AF: 0.0840 AC: 6663

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CPZ-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.4
DANN	Benign	0.90
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.071
Sift	Benign	0.24	T;D
Sift4G	Benign	0.21	T;T
Polyphen		0.93	P;D
Vest4		0.083
MPC		0.0030
ClinPred		0.020	T
GERP RS		0.83
Varity_R		0.30
gMVP		0.71

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: rs79736750; hg19: chr4-8594616;