4-8599461-C-T

Position:

chr4-8599461-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001014447.3(CPZ):c.97C>T(p.His33Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,611,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CPZ
NM_001014447.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.586

Variant links:

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 links:

CPZ (HGNC:):

CPZ links:

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]

GPR78 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03200063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPZ	NM_001014447.3 linkuse as main transcript	c.97C>T	p.His33Tyr	missense_variant	2/11	ENST00000360986.9	NP_001014447.2	Q66K79-1A0A384MDV6
CPZ	NM_001014448.3 linkuse as main transcript	c.-578C>T		5_prime_UTR_variant	2/11		NP_001014448.2	Q66K79-3
CPZ	NM_003652.4 linkuse as main transcript	c.89-1662C>T		intron_variant			NP_003643.3	Q66K79-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986.9 linkuse as main transcript	c.97C>T	p.His33Tyr	missense_variant	2/11	1	NM_001014447.3	ENSP00000354255.4		Q66K79-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000769

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

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248622

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000437

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1459482

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

725730

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000278

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2024

The c.97C>T (p.H33Y) alteration is located in exon 2 (coding exon 2) of the CPZ gene. This alteration results from a C to T substitution at nucleotide position 97, causing the histidine (H) at amino acid position 33 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.016

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.45

M_CAP

Benign

0.0063

MetaRNN

Benign

0.032

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.82

REVEL

Benign

0.010

Sift

Benign

0.34

Sift4G

Benign

0.37

Polyphen

0.10

Vest4

0.19

MVP

0.43

MPC

0.0034

ClinPred

0.032

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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