12-18688215-T-C

Variant names:

• chr12-18688215-T-C
• rs757326350
• NM_033123.4:c.1465A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_033123.4(PLCZ1):​c.1465A>G​(p.Ile489Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,114 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I489F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLCZ1 NM_033123.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50
• Publications: 17 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-18688215-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 271283.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCZ1	NM_033123.4	c.1465A>G	p.Ile489Val	missense_variant	Exon 13 of 15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCZ1	ENST00000266505.12	c.1465A>G	p.Ile489Val	missense_variant	Exon 13 of 15	1	NM_033123.4	ENSP00000266505.7
PLCZ1	ENST00000648272.1	c.1588A>G	p.Ile530Val	missense_variant	Exon 12 of 14			ENSP00000497636.1
PLCZ1	ENST00000539875.5	c.886A>G	p.Ile296Val	missense_variant	Exon 9 of 11	1		ENSP00000445026.1
PLCZ1	ENST00000318197.10	n.*1330A>G		non_coding_transcript_exon_variant	Exon 13 of 15	1		ENSP00000326397.6
PLCZ1	ENST00000318197.10	n.*1330A>G		3_prime_UTR_variant	Exon 13 of 15	1		ENSP00000326397.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248072 AF XY: 0.00000744

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: 0.00000137 AC: 2 AN: 1455114 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724212

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108838

Other (OTH) AF: 0.00 AC: 0 AN: 60174

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;.;T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Uncertain	-0.026	T
MutationAssessor	Uncertain	2.4	.;.;M;.;.
PhyloP100		5.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.99	.;N;N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0070	.;D;D;D;D
Sift4G	Uncertain	0.028	.;D;D;D;.
Polyphen		1.0	.;D;D;.;.
Vest4		0.53, 0.45, 0.52
MutPred		0.57		.;.;Gain of catalytic residue at Q493 (P = 0.0107);.;.;
MVP		0.81
MPC		0.12
ClinPred		0.81	D
GERP RS		5.7
Varity_R		0.60
gMVP		0.36
Mutation Taster		=251/49	polymorphism

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

Other links and lift over

dbSNP: rs757326350; hg19: chr12-18841149;