12-18688211-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033123.4(PLCZ1):c.1469G>A(p.Ser490Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000756 in 1,455,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

PLCZ1
NM_033123.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

Publications

0 publications found

Variant links:

Genes affected

PLCZ1 (HGNC:19218): (phospholipase C zeta 1) The protein encoded by this gene is a member of the phosphoinositide-specific phospholipase C family. Members in this family, classified into six isotypes that are tissue- and organ-specific, hydrolyze phosphatidylinositol 4,5-bisphosphate just before the phosphate group to yield diacylglycerol and inositol 1,4,5-trisphosphate. This protein localizes to the acrosome in spermatozoa and elicits Ca(2+) oscillations and egg activation during fertilization that leads to early embryonic development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

PLCZ1 links:

PIK3C2G (HGNC:8973): (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 gamma) The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. This gene may play a role in several diseases, including type II diabetes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

PIK3C2G links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCZ1	NM_033123.4 link	c.1469G>A	p.Ser490Asn	missense_variant	Exon 13 of 15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLCZ1	ENST00000266505.12 link	c.1469G>A	p.Ser490Asn	missense_variant	Exon 13 of 15	1	NM_033123.4	ENSP00000266505.7	Q86YW0-1
PLCZ1	ENST00000648272.1 link	c.1592G>A	p.Ser531Asn	missense_variant	Exon 12 of 14			ENSP00000497636.1	A0A3B3ISW9
PLCZ1	ENST00000539875.5 link	c.890G>A	p.Ser297Asn	missense_variant	Exon 9 of 11	1		ENSP00000445026.1	Q86YW0-2
PLCZ1	ENST00000318197.10 link	n.*1334G>A		non_coding_transcript_exon_variant	Exon 13 of 15	1		ENSP00000326397.6	F5H474
PLCZ1	ENST00000318197.10 link	n.*1334G>A		3_prime_UTR_variant	Exon 13 of 15	1		ENSP00000326397.6	F5H474

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

248426

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000756

AC:

AN:

1455894

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33314

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26042

East Asian (EAS)

AF:

0.00

AC:

AN:

39512

South Asian (SAS)

AF:

0.00

AC:

AN:

86000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000901

AC:

AN:

1109290

Other (OTH)

AF:

0.0000166

AC:

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 15, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1469G>A (p.S490N) alteration is located in exon 13 (coding exon 12) of the PLCZ1 gene. This alteration results from a G to A substitution at nucleotide position 1469, causing the serine (S) at amino acid position 490 to be replaced by an asparagine (N). 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

Pathogenic

0.85

BayesDel_addAF

Benign

0.0066

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

.;.;D;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.62

D;D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

3.4

.;.;M;.;.

PhyloP100

3.7

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

.;D;D;D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0010

.;D;D;D;.

Polyphen

1.0

.;D;D;.;.

Vest4

0.74, 0.56, 0.73

MutPred

0.46

.;.;Gain of catalytic residue at L494 (P = 0);.;.;

MVP

0.85

MPC

0.14

ClinPred

1.0

GERP RS

5.7

Varity_R

0.91

gMVP

0.72

Mutation Taster

=222/78

polymorphism

(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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12-18688211-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over