12-18699797-G-C

Variant names:

• chr12-18699797-G-C
• rs138740994
• NM_033123.4:c.1171C>G

Variant summary

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

The NM_033123.4(PLCZ1):​c.1171C>G​(p.Arg391Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 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. R391Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLCZ1 NM_033123.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.214
• 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 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	c.1171C>G	p.Arg391Gly	missense_variant	Exon 10 of 15	ENST00000266505.12	NP_149114.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCZ1	ENST00000266505.12	c.1171C>G	p.Arg391Gly	missense_variant	Exon 10 of 15	1	NM_033123.4	ENSP00000266505.7
PLCZ1	ENST00000648272.1	c.1294C>G	p.Arg432Gly	missense_variant	Exon 9 of 14			ENSP00000497636.1
PLCZ1	ENST00000539875.5	c.592C>G	p.Arg198Gly	missense_variant	Exon 6 of 11	1		ENSP00000445026.1
PLCZ1	ENST00000318197.10	n.*1036C>G		non_coding_transcript_exon_variant	Exon 10 of 15	1		ENSP00000326397.6
PLCZ1	ENST00000318197.10	n.*1036C>G		3_prime_UTR_variant	Exon 10 of 15	1		ENSP00000326397.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460718 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726766

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111224

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.073	.;.;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.070	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.47	.;.;N;.;.
PhyloP100		-0.21
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	.;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.14	.;T;D;T;T
Sift4G	Uncertain	0.044	.;D;D;T;.
Polyphen		0.55, 0.58	.;P;P;.;.
Vest4		0.39, 0.36, 0.37
MutPred		0.56		.;.;Gain of catalytic residue at E394 (P = 0.0084);.;.;
MVP		0.31
MPC		0.041
ClinPred		0.18	T
GERP RS		-2.2
Varity_R		0.067
gMVP		0.23
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.45		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138740994; hg19: chr12-18852731;