Genetic Variant CPZ:c.89-1713G>C (chr4-8597740-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001014447.3(CPZ):c.89-1713G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 152,232 control chromosomes in the GnomAD database, including 12,830 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.40 ( 12827 hom., cov: 34)

Exomes 𝑓: 0.44 ( 3 hom. )

Consequence

CPZ
NM_001014447.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.33

Publications

2 publications found

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:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CPZ	NM_001014447.3 link	c.89-1713G>C	intron_variant	Intron 1 of 10	ENST00000360986.9	NP_001014447.2	Q66K79-1A0A384MDV6
CPZ	NM_003652.4 link	c.89-3383G>C	intron_variant	Intron 1 of 9		NP_003643.3	Q66K79-2
CPZ	NM_001014448.3 link	c.-586-1713G>C	intron_variant	Intron 1 of 10		NP_001014448.2	Q66K79-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPZ	ENST00000360986.9 link	c.89-1713G>C		intron_variant	Intron 1 of 10	1	NM_001014447.3	ENSP00000354255.4		Q66K79-1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60490

AN:

152080

Hom.:

12826

Cov.:

show subpopulations

Gnomad AFR

AF:

0.262

Gnomad AMI

AF:

0.497

Gnomad AMR

AF:

0.439

Gnomad ASJ

AF:

0.584

Gnomad EAS

AF:

0.613

Gnomad SAS

AF:

0.525

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.432

Gnomad OTH

AF:

0.456

GnomAD4 exome

AF:

0.441

AC:

AN:

Hom.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.333

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.625

AC:

AN:

Other (OTH)

AF:

0.167

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.547

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.398

AC:

60514

AN:

152198

Hom.:

12827

Cov.:

AF XY:

0.402

AC XY:

29942

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.262

AC:

10902

AN:

41536

American (AMR)

AF:

0.440

AC:

6726

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

2027

AN:

3470

East Asian (EAS)

AF:

0.614

AC:

3165

AN:

5158

South Asian (SAS)

AF:

0.524

AC:

2529

AN:

4822

European-Finnish (FIN)

AF:

0.399

AC:

4228

AN:

10602

Middle Eastern (MID)

AF:

0.483

AC:

142

AN:

294

European-Non Finnish (NFE)

AF:

0.432

AC:

29383

AN:

67990

Other (OTH)

AF:

0.454

AC:

959

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1873

3745

5618

7490

9363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.228

Hom.:

498

Bravo

AF:

0.396

Asia WGS

AF:

0.544

AC:

1893

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.21

(source)

DANN

Benign

0.47

PhyloP100

-3.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over