12-18684180-C-A

Variant names:

• chr12-18684180-C-A
• NM_033123.4:c.1691G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033123.4(PLCZ1):​c.1691G>T​(p.Gly564Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCZ1 NM_033123.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.228
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23413703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCZ1	NM_033123.4	c.1691G>T	p.Gly564Val	missense_variant	Exon 14 of 15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCZ1	ENST00000266505.12	c.1691G>T	p.Gly564Val	missense_variant	Exon 14 of 15	1	NM_033123.4	ENSP00000266505.7
PLCZ1	ENST00000648272.1	c.1814G>T	p.Gly605Val	missense_variant	Exon 13 of 14			ENSP00000497636.1
PLCZ1	ENST00000539875.5	c.1112G>T	p.Gly371Val	missense_variant	Exon 10 of 11	1		ENSP00000445026.1
PLCZ1	ENST00000318197.10	n.*1556G>T		non_coding_transcript_exon_variant	Exon 14 of 15	1		ENSP00000326397.6
PLCZ1	ENST00000318197.10	n.*1556G>T		3_prime_UTR_variant	Exon 14 of 15	1		ENSP00000326397.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1691G>T (p.G564V) alteration is located in exon 14 (coding exon 13) of the PLCZ1 gene. This alteration results from a G to T substitution at nucleotide position 1691, causing the glycine (G) at amino acid position 564 to be replaced by a valine (V). 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	0.17
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.20	.;.;.;T;.
Eigen	Benign	-0.013
Eigen_PC	Benign	-0.076
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.7	.;.;.;L;.
PhyloP100		0.23
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	.;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.073	.;T;T;T;D
Sift4G	Benign	0.25	.;T;D;T;T
Polyphen		0.84, 0.72	.;.;P;P;.
Vest4		0.21, 0.27, 0.24, 0.26
MutPred		0.54		.;.;.;Gain of catalytic residue at I562 (P = 0);.;
MVP		0.73
MPC		0.053
ClinPred		0.65	D
GERP RS		2.1
Varity_R		0.18
gMVP		0.49
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

hg19: chr12-18837114;